Foam prepared from nanoemulsions and uses

ABSTRACT

The present invention provides a foamable composition for administration to the skin, body surface, body cavity or mucosal surface, e.g., the mucosa of the nose, mouth, eye, ear, respiratory system, vagina or rectum, and methods of using such a composition to treat, alleviate, or prevent a disorder of the skin, body cavity, or mucosal surface. The foamable oil in water nano emulsion composition includes: (a) a nano oil globule system, comprising substantially of sub-micron oil globules; (b) about 0.1% to about 5% by weight of at least one stabilizing agent selected from (i) a non-ionic surfactant, (ii) an ionic surfactant, or (iii) a polymeric agent; and (c) a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition, water and optional ingredients. Upon release from an aerosol container, the foamable composition forms and expanded foam suitable for topical administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is continuation of and claims benefit of priority toU.S. application Ser. No. 11/975,621, filed on Oct. 19, 2007, which is acontinuation-in-part application of co-pending U.S. patent applicationSer. No. 11/389,742, filed on Mar. 27, 2006, which (i) is acontinuation-in-part of Ser. No. 10/911,367, filed on Aug. 4, 2004,which claims priority under 35 U.S.C. §119(e) to U.S. ProvisionalApplication No. 60/492,385, filed on Aug. 4, 2003; (ii) claims priorityunder 35 U.S.C. §119(e) to U.S. Provisional Application No. 60/717,058,filed Sep. 14, 2005 and (iii) is a continuation-in-part of Ser. No.10/532,618, filed on Dec. 22, 2005, which is a continuation-in-part ofPCT/IB03/05527, filed on Oct. 24, 2003, which claims priority to U.S.Provisional Application No. 60/429,546, filed on Nov. 29, 2002 andIsraeli Application No. 152486, filed on Oct. 25, 2002, all of which areincorporated in their entirety by reference.

BACKGROUND

Foams and, in particular, foam emulsions are complex dispersion systemswhich do not form under all circumstances. Slight shifts in foamemulsion composition, such as by the addition of active ingredients, maydestabilize the foam.

Micro emulsions and nano emulsion can be monophasic, transparent (orslightly translucent) dispersions of oil and water. Unlike conventionalemulsions, micro emulsions and nano emulsion can be thermodynamicallystable, making them a favorable vehicle for pharmaceutical compositions,which have to maintain stability for long periods of time. Microemulsions are sometimes said to be misleadingly called micro emulsionssince they can form clear solutions devoid of the opaque color ofregular emulsions. Micro emulsions can be oil external, water externaland middle phase. Nano emulsions in contrast can be very fine oil inwater dispersions. Droplet diameters can be as low as smaller than 100nm. They can be in a metastable state and their structure can depend onthe system history. They can be very fragile systems and can thereforebe problematic in trying to formulate pharmaceutical and cosmeticcompositions. If destabilized they can become opaque or exhibitcreaming. On the other hand they can provide useful applications in skincare in that they may exhibit good textural and sensural properties dueto the very fine droplet or globule size. Likewise for similar reasonsthey may provide more rapid penetration than conventional emulsions andcan offer hydrating capabilities.

Foams are very complex and sensitive systems and are not formed at will.Mere addition of basic ingredients like oil, water, surfactant andpropellant is far from sufficient to produce foams of quality that arehomogenous, stable, breakable upon mechanical force and can be used toprovide a shelf stable pharmaceutical or cosmetic composition. Smalldeviations may lead to foam collapse. Much consideration needs to begiven to facilitate the introduction of an active agent, such asexamining compatibility and non reactivity with the various excipientsand container and determining shelf life chemical stability. All theseconsiderations become a greater and more non obvious challenge whentrying to formulate a foamable nano-emulsion composition, which demandsthe symbiosis and compatibility of a complex, sensitive system with afragile and metastable system to produce a homogenous, stable, breakableshelf stable nano foam. Moreover, nano droplets can be sterilized byfiltration.

Storage triacylglycerols (TAG) in plant seeds are present in smalldiscrete intracellular organelles ranging from 1 to 2 μm, which arecalled oil-bodies. An oil body has a matrix of TAG, which is surroundedby phospholipids (PL) and alkaline proteins, termed oleosins. Oleosinsare highly lipophilic proteins, are expressed at high levels in manyseeds and are specifically targeted to oil-bodies. Oil-bodies areabundant in plant seeds and are among the simplest organelles present ineukaryotes. They are remarkably stable both inside the cells and inisolated preparations.

Oil bodies are also termed in the literature as “oleosomes”, “lipidbodies” and “spherosomes”.

SUMMARY

The present invention relates to foamable compositions comprising oil inwater nano emulsions which produce foam having an improved bubble sizecompared to the foam produced form a regular oil in water emulsion; tomethods of treating, alleviating or preventing a disorder of the skin,body cavity or mucosal surface using the foamable compositions; and tomethods of producing a foam having an improved bubble size.

In one aspect, the present invention provides a foamable oil in waternano emulsion composition comprising: (a) a nano oil globule system,comprising substantially of sub-micron oil globules; (b) about 0.1% toabout 5% by weight of at least one stabilizing agent, selected from thegroup consisting of (i) a non-ionic surfactant, (ii) an ionicsurfactant, and (iii) a polymeric agent; (c) water; and (d) a liquefiedor compressed gas propellant at a concentration of about 3% to about 25%by weight of the total composition, wherein the oil, stabilizer andwater are selected to provide a composition that is substantiallyhomogenous and resistant to aging; wherein the composition is containedin a pressurized container is substantially flowable and provides abreakable foam upon release, which is thermally stable, yet breaks undersheer force; and wherein the bubble size of the resultant foam issignificantly greater than the bubble size of the resultant foam from acomposition with the same ingredients which has not been subject to nanoprocessing.

In another aspect, the present invention provides a foamable oil inwater nano emulsion composition comprising: (a) a nano oil globulesystem, comprising substantially of sub-micron oil globules; (b) about0.1% to about 5% by weight of at least one stabilizing agent, selectedfrom the group consisting of (i) a non-ionic surfactant, (ii) an ionicsurfactant, and (iii) a polymeric agent; (c) water; and (d) a liquefiedor compressed gas propellant at a concentration of about 3% to about 25%by weight of the total composition, wherein the oil, stabilizer andwater are selected to provide a composition that is substantiallyhomogenous and resistant to aging and wherein the viscosity of the nanoemulsion is substantially reduced than the viscosity of the a macroemulsion having substaintially the same composition; wherein thecomposition is contained in a pressurized container is substantiallyflowable and provides a breakable foam upon release, which is thermallystable, yet breaks under sheer forcea; and wherein the bubble size ofthe resultant foam is significantly greater than the bubble size of theresultant foam from a composition with the same ingredients which hasnot been subject to nano processing.

In yet another aspect, the present invention provides a foamable oil inwater nano emulsion composition comprising: (a) a nano oil globulesystem, comprising substantially of sub-micron oil globules; (b) about0.1% to about 5% by weight of at least one stabilizing agent, selectedfrom the group consisting of (i) a non-ionic surfactant, (ii) an ionicsurfactant, and (iii) a polymeric agent; (c) water; and (d) a liquefiedor compressed gas propellant at a concentration of about 3% to about 25%by weight of the total composition, wherein the oil, stabilizer andwater are selected to provide a composition that is substantiallyhomogenous and resistant to aging; wherein the composition prior toaddition of propellant is translucent with a blue tint; wherein if thecomposition is contained in a pressurized container and furthercomprises a liquefied hydrocarbon gas propellant at a concentration ofabout 3% to about 35% by weight of the total composition it issubstantially flowable and provides a breakable foam upon release, whichis thermally stable, yet breaks under sheer force; and wherein thebubble size of the resultant foam is significantly greater than thebubble size of the resultant foam from a composition with the sameingredients which has not been subject to nano processing.

In one aspect there is provided a foamable oil in water nano emulsion,composition containing small oil globules including an oil globulesystem, selected from the group consisting of oil bodies and sub-micronoil globules, about 0.1% to about 5% by weight of at least onestabilizing agent selected from the group consisting of a non-ionicsurfactant having an HLB value between 9 and 16, an ionic surfactant,and a polymeric agent water, as well as a liquefied or compressed gaspropellant at a concentration of about 3% to about 25% by weight of thetotal composition.

According to further embodiments of the foamable composition of presentinvention, the oil globule system consists of oil bodies and thestabilizing agent consists of a polymeric agent.

According to still further embodiments of the foamable composition ofpresent invention, the oil globule system consists of oil bodies and thestabilizing agent consists of an ionic surfactant.

According to yet further embodiments of the present invention thesurface-active agent is a phospholipid.

According to still further embodiments of the present invention, the oilbodies are discrete oleaginous particles ranging from about 1 to about 3μm in dimension. Oil bodies contain triacylclycerols (TAG), surroundedby phospholipids (PL) and oleosins.

According to further embodiments of the present invention, thephospholipids are selected from the group consisting ofphosphatidylethanolamine, phosphatidylcholine, lecithin,phosphatidylserine, phosphatidylglycerol and phosphatidylinositol.

According to still further embodiments of the present invention, theoleosins are highly lipophilic small proteins of about 25 to 26 kD.

In one or more embodiments, the oil bodies are derived from the seeds ofa plant, selected from the group consisting of almond (Prunus dulcis),anise (Pimpinella anisum), avocado (Persea spp.), beach nut (Fagussylvatica), borage (also known as evening primrose) (Boragioofficinalis), Brazil nut (Bertholetia excelsa), candle nut (Aleuritistiglium), carapa (Carapa guineensis), cashew nut (Ancardiumoccidentale), castor (Ricinus communis), coconut (Cocus nucifera),coriander (Coriandrum sativum), cottonseed (Gossypium spp.), crambe(Crambe abyssinica), Crepis alpina, croton (Croton tiglium), Cupheaspp., dill (Anethum gravealis), Euphorbia lagascae, Dimorphotecapluvialis, false flax (Camolina sativa), fennel (Foeniculum vulgaris),groundnut (Arachis hypogaea), hazelnut (coryllus avellana), hemp(Cannabis sativa), honesty plant (lunnaria annua), jojoba (Simmiondsiachinensis), kapok fruit (Ceiba pentandra), kukui nut (Aleuritismoluccana), Lesquerella spp., linseed/flax (Linum usitatissimum),macademia nut (Macademia spp.), maize (Zea mays), meadow foam(Limnanthes alba), mustard (Brassica spp. and Sinapis alba), oil palm(Elaeis guineeis), oiticia (Licania rigida), paw paw (Assimina triloba),pecan (Juglandaceae ssp.), perilla (Perilla futescens), physic nut(Gairopha curcas), pilinut (Canariuim ovatum), pine nut (pine spp.),pistachio (Pistachia vera), pongam (Bongamin glabra), poppy seed(Papaver soniferum), rapeseed (Brassica spp.), safflower (Carthamustinctorius), sesame seed (Sesamum indicum), soybean (Glycine max),squash (Cucurbita maxima), sal tree (Shorea rubusha), Stokes aster(Stokesia laevis), sunflower (Helianthus annuus), tukuma (Astocaryaspp.), tung nut (Aleuritis cordata), and vernolnia (Verzoniagalamensis).

According to a further embodiment of the foamable composition, thefoamable composition further includes about 0.1% to about 5% by weightof a foam adjuvant selected from the group consisting of a fatty alcoholhaving 15 or more carbons in their carbon chain, a fatty acid having 16or more carbons in their carbon chain, fatty alcohols derived frombeeswax and including a mixture of alcohols, a majority of which has atleast 20 carbon atoms in their carbon chain, a fatty alcohol having atleast one double bond, a fatty acid having at least one double bond, abranched fatty alcohol, a branched fatty acid, and a fatty acidsubstituted with a hydroxyl group and mixtures thereof.

According to further embodiments of the present invention, the foamablecomposition is substantially alcohol-free.

According to still further embodiments of the present invention, theconcentration range of oil globules is selected from the group of (i)about 0.05% and about 2% and about 5%, (ii) about 2% (iii) about 5% andabout 12%, and (iv) about 12% and about 24%.

According to further embodiments of the present invention, the polymericagent is selected from the group consisting of a water-soluble celluloseether and naturally-occurring polymeric material.

According to still further embodiments of the present invention, thewater-soluble cellulose ether is selected from the group consisting ofmethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose(Methocel), hydroxyethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethylcellulose, carboxymethylhydroxyethylcellulose, xanthan gum,guar gum, carrageenin gum, locust bean gum and tragacanth gum.

According to yet further embodiments of the present invention, thefoamable composition further includes at least one therapeutic agent.

According to further embodiments of the present invention, thetherapeutic agent is selected from the group consisting of ananti-infective, an antibiotic, an antibacterial agent, an antifungalagent, an antiviral agent, an antiparasitic agent, an steroidalanti-inflammatory agent, an immunosuppressive agent, an immunomodulator,an immunoregulating agent, a hormonal agent, vitamin A, a vitamin Aderivative, vitamin B, a vitamin B derivative, vitamin C, a vitamin Cderivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin Ederivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin Kderivative, a wound healing agent, a disinfectant, an anesthetic, anantiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid,a beta-hydroxy acid, a protein, a peptide, a neuropeptide, a allergen,an immunogenic substance, a haptene, an oxidizing agen, an antioxidant,a dicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaricacid, a retinoid, an antiproliferative agent, an anticancer agent, aphotodynamic therapy agent, an anti-wrinkle agent, a radical scavenger,a metal oxide (e.g., titanium dioxide, zinc oxide, zirconium oxide, ironoxide, silicone oxide, an anti wrinkle agent, a skin whitening agent, askin protective agent, a masking agent, an anti-wart agent, a refattingagent, a lubricating agent and mixtures thereof).

According to still further embodiments of the present invention, thetherapeutic agent is selected from the components of the oil bodies orsub-micron oil globules.

According to further embodiments of the present invention, thetherapeutic agent is suitable to treat a disorder selected from thegroup consisting of dermatological disorder, a cosmetic disorder, agynecological disorder, a disorder of a body cavity, wound and burn.

In a further aspect, the present invention provides methods of treating,alleviating or preventing a disorder of the skin, body cavity or mucosalsurface using the foamable compositions described herein.

In one aspect, the present invention provides a method of treating,alleviating or preventing a disorder of the skin, body cavity or mucosalsurface, wherein said disorder involves insufficient hydration of skinor a mucosal surface as one of its etiological factors, comprising:administering topically to a subject having said disorder, a foamedcomposition comprising: (a) a nano oil globule system, comprisingsubstantially of sub-micron oil globules; (b) about 0.1% to about 5% byweight of at least one stabilizing agent, selected from the groupconsisting of (i) a non-ionic surfactant, (ii) an ionic surfactant, and(iii) a polymeric agent; (c) water; and (d) a liquefied or compressedgas propellant at a concentration of about 3% to about 25% by weight ofthe total composition, wherein the oil, stabilizer and water areselected to provide a composition that is substantially homogenous andresistant to aging and wherein the viscosity of the pre foam formulationremains substantially high after it has been subject to nano processing;wherein the composition is contained in a pressurized container issubstantially flowable and provides a breakable foam upon release, whichis thermally stable, yet breaks under sheer force; and wherein thebubble size of the resultant foam is significantly greater than thebubble size of the resultant foam from a composition with the sameingredients which has not been subject to nano processing.

According to a further embodiment of the present invention, there isprovided a method of treating, alleviating or preventing a disorder ofthe skin, body cavity or mucosal surface, wherein the disorder involvesinsufficient hydration of skin or a mucosal surface as one of itsetiological factors. The method includes administering topically to asubject having the disorder, a foamed composition containing (a) a nanooil globule system, comprising substantially of sub-micron oil globules;(b) about 0.1% to about 5% by weight of at least one stabilizing agent,selected from the group consisting of (i) a non-ionic surfactant, (ii)an ionic surfactant, and (iii) a polymeric agent; (c) water; and (d) aliquefied or compressed gas propellant at a concentration of about 3% toabout 25% by weight of the total composition.

According to a further embodiment of the method, the composition furtherincludes an active agent effective to treat a disorder, and wherein thedisorder is selected from the group consisting of a vaginal disorder, avulvar disorder, an anal disorder, a disorder of a body cavity, an eardisorder, a disorder of the nose, a disorder of the respiratory system,a bacterial infection, fungal infection, viral infection, dermatosis,dermatitis, parasitic infections, disorders of hair follicles andsebaceous glands, scaling papular diseases, benign tumors, malignanttumors, reactions to sunlight, bullous diseases, pigmentation disorders,disorders of cornification, pressure sores, disorders of sweating,inflammatory reactions, xerosis, ichthyosis, allergy, burn, wound, cut,chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS,human papillomavirus (HPV), genital warts, bacterial vaginosis,candidiasis, chancroid, granuloma Inguinale, lymphogranloma venereum,mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcalurethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvarpain, yeast infection, vulvar dystrophy, vulvar intraepithelialneoplasia (VIN), contact dermatitis, osteoarthritis, joint pain,hormonal disorder, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum.

According to a further embodiment of the present invention, there isprovided a method to promote the penetration of an active agent into thesurface layers of the skin and mucosal membranes. The method includesapplying a foamable composition to the surface layers of a skin ormucosal membrane the foamable composition, comprising (a) a nano oilglobule system, comprising substantially of sub-micron oil globules; (b)about 0.1% to about 5% by weight of at least one stabilizing agent,selected from the group consisting of (i) a non-ionic surfactant, (ii)an ionic surfactant, and (iii) a polymeric agent; (c) water; and (d) aliquefied or compressed gas propellant at a concentration of about 3% toabout 25% by weight of the total composition.

According to a further embodiment of the present invention, there isprovided a method of treating, alleviating or preventing a disorder ofthe skin, body cavity or mucosal surface, wherein said disorder involvesinsufficient hydration of skin or a mucosal surface as one of itsetiological factors. The method includes applying a foamable compositionto the surface layers of a skin, body cavity or mucosal membrane thefoamable composition, comprising (a) a nano oil globule system,comprising substantially of sub-micron oil globules; (b) about 0.1% toabout 5% by weight of at least one stabilizing agent, selected from thegroup consisting of (i) a non-ionic surfactant, (ii) an ionicsurfactant, and (iii) a polymeric agent; (c) water; and (d) a liquefiedor compressed gas propellant at a concentration of about 3% to about 25%by weight of the total composition. In certain embodiments, thecomposition prior to addition of propellant is translucent with a bluetint.

In one aspect, the present invention provides a method of producing afoam having improved foam bubble size comprising: (i) preparing a prefoam oil in water emulsion formulation, wherein the pre foam oilcomprises (a) oil globules; (b) about 0.1% to about 5% by weight of atleast one stabilizing agent selected from the group consisting of anon-ionic surfactant, an ionic surfactant, and a polymeric agent; and(c) water; (ii) subjecting the pre foam formulation to high pressuremechanical stress to produce a nano emulsion; (iii) storing the nanoemulsion in a sealed pressurized container that further comprises aliquefied hydrocarbon gas propellant at a concentration of about 3% toabout 25% by weight of the total composition and having an outletcapable of releasing the pressurized product as a foam; and (iv)releasing the foam, wherein the bubble size of the resultant foam issignificantly greater than the bubble size of a resultant foam from thepre foam oil in water emulsion formulation stored in a sealedpressurized container that further comprises a liquefied hydrocarbon gaspropellant at a concentration of about 3% to about 25% by weight of thetotal composition and having an outlet capable of releasing thepressurized product as a foam.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows pictures of a sample section of the foam produced fromcomposition 13 of Example 9 before nano processing.

FIG. 1B shows pictures of a sample section of the foam produced fromcomposition 13 of Example 9 after 6 cycles of nano processing.

FIG. 2A shows pictures of a sample section of the foam produced fromcomposition 11 of Example 8 before nano processing.

FIG. 2B shows pictures of a sample section of the foam produced fromcomposition 11 of Example 8 after 6 cycles of nano processing.

FIG. 3A shows pictures of a sample section of the foam produced fromcomposition 7 of Example 7 before nano processing.

FIG. 3B shows pictures of a sample section of the foam produced fromcomposition 10 of Example 7 after 6 cycles of nano processing.

FIG. 4A shows pictures of a sample section of the foam produced fromcomposition 14 of Example 9 before nano processing.

FIG. 4B shows pictures of a sample section of the foam produced fromcomposition 14 of Example 9 after 6 cycles of nano processing.

FIG. 5A shows pictures of a sample section of the foam produced fromcomposition 15 of Example 9 before nano processing, which foam comprisespropellant having 50% more pressure than that of the foam as shown inFIG. 5B.

FIG. 5B shows pictures of a sample section of the foam produced fromcomposition 15 of Example 9 before nano processing.

FIG. 5C shows pictures of a sample section of the foam produced fromcomposition 15 of Example 9 after 6 cycles of nano processing.

DETAILED DESCRIPTION

The present invention provides a foamable oil in water nano emulsion,composition including small oil globules. As used herein, the termsdroplets, globules and particles, when referencing an emulsion, are usedinterchangeably. All % values are provided on a weight (w/w) basis.

According to one or more embodiments of the present invention, thefoamable oil in water nano emulsion composition is intended foradministration to the skin, a body surface, a body cavity or mucosalsurface, e.g., the mucosa of the nose, mouth, eye, ear, respiratorysystem, vagina or rectum (severally and interchangeably termed herein“target site”).

In an embodiment there is provided a foamable oil in water nano emulsioncomposition comprising:

-   -   (a) A nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent, selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent;    -   (c) water; and    -   (d) a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging;

-   wherein the composition is contained in a pressurized container is    substantially flowable and provides a breakable foam upon release,    which is thermally stable, yet breaks under sheer force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In another embodiment the oil globule system consists of oil globuleswith an average diameter size in the range of about 1000 nanometers toabout 10 nanometers; and the stabilizing agent consists of a polymericagent.

In an embodiment there is provided a foamable oil in water nano emulsioncomposition comprising a non-ionic surfactant having an HLB valuebetween 9 and 16; and/or an ionic surfactant.

In another embodiment the oil globules are discrete particles with themajority having a size ranging from about 300 to about 20 nanometers inat least one dimension.

In another embodiment the oil globule system consists of sub-micron oilglobules; and the stabilizing agent consists of a surfactant, having anHLB value or a mean HLB value between 9 and 16.

In a further embodiment the ratio of surfactant to oil is high being inthe range of the order of about 1:1 to about 1:10

In another embodiment the sub-micron oil globules contain at least oneorganic carrier selected from the group consisting of a hydrophobicorganic carrier, a polar solvent, an emollient and mixtures thereof.

In a further embodiment said submicron oil globules are about 50% toabout 100% of the composition.

In another embodiment the sub-micron oil globules have a number-averagesize range, selected from (i) 40 nm to 1,000 nm. (ii) 40 nm to 500 nm;(iii) 40 nm to 200 nm; (iv) 40 nm to 100 nm (v) less than 500 nm; (vi)less than 200 nm; and (vii) less than 100 nm.

In an embodiment the sub-micron oil globules are produced by high sheerhomogenization.

In an embodiment there is provided a foamable oil in water nano emulsioncomposition further comprising about 0.1% to about 5% by weight of afoam adjuvant selected from the group consisting of a fatty alcoholhaving 15 or more carbons in their carbon chain; a fatty acid having 16or more carbons in their carbon chain; fatty alcohols derived frombeeswax and including a mixture of alcohols, a majority of which has atleast 20 carbon atoms in their carbon chain; a fatty alcohol having atleast one double bond; a fatty acid having at least one double bond; abranched fatty alcohol; a branched fatty acid; and a fatty acidsubstituted with a hydroxyl group and mixtures thereof.

In an embodiment said foamable composition is substantiallyalcohol-free.

In an embodiment there is provided a foamable oil in water nano emulsioncomposition further containing at least one therapeutic agent.

In an embodiment the therapeutic agent is selected from the groupconsisting of an anti-infective, an antibiotic, an antibacterial agent,an antifungal agent, an antiviral agent, an antiparasitic agent, ansteroidal antiinflammatory agent, an immunosuppressive agent, animmunomodulator, an immunoregulating agent, a hormonal agent, vitamin A,a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, avitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, avitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, avitamin K derivative, a wound healing agent, a disinfectant, ananesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid,glycolic acid, a beta-hydroxy acid, a protein, a peptide, aneuropeptide, a allergen, an immunogenic substance, a haptene, anoxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid,sebacic acid, adipic acid, fumaric acid, a retinoid, anantiproliferative agent, an anticancer agent, a photodynamic therapyagent, an anti-wrinkle agent, a radical scavenger, a metal oxide (e.g.,titanium dioxide, zinc oxide, zirconium oxide, iron oxide), siliconeoxide, an anti wrinkle agent, a skin whitening agent, a skin protectiveagent, a masking agent, an anti-wart agent, a refatting agent, alubricating agent and mixtures thereof.

In an embodiment the therapeutic agent is suitable to treat a disorder,selected from a dermatological disorder, a cosmetic disorder, agynecological disorder, a disorder of a body cavity, wound and burn.

In an embodiment there is provided a foamable oil in water nano emulsioncomposition wherein the HLB or mean HLB value of said non-ionicsurfactant is between about 2 and about 9.

In an embodiment the stabilizing agent is a polymeric agent selectedfrom the group consisting of a water-soluble cellulose ethernaturally-occurring polymeric material, microcrystalline cellulose,hydrophobically-modified ethoxylated urethane, and a carbomer.

In an embodiment the water-soluble cellulose ether is selected from thegroup consisting of methylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose (Methocel), hydroxyethyl cellulose,methylhydroxyethylcellulose, methylhydroxypropylcellulose,hydroxyethylcarboxymethylcellulose, carboxymethylcellulose,carboxymethylhydroxyethylcellulose, xanthan gum, guar gum, carrageeningum, locust bean gum and tragacanth gum.

In an embodiment the surfactant is selected from the group consisting ofsteareth 2, steareth 21, ceteth-20, span 80, behenyl alcohol, glycerylmonostearate, PEG 40 stearate, polyoxyl 100 monostearate, methyl glucoseseasquit stearate and polysorbate 80.

In an embodiment there is provided a foamable oil in water nano emulsioncomposition wherein the density of the foam is selected from the groupconsisting of (1) less than 0.12 g/mL; (2) the range between 0.02 and0.12; (3) the range between 0.04 and 0.10; (4) the range between 0.06and 0.10.

In an embodiment there is provided a foamable oil in water nano emulsioncomposition comprising:

-   -   (a) A nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent, selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent;    -   (c) water; and    -   (d) a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging    and wherein the viscosity of the pre foam formulation is    substantially reduced after it has been subject to nano processing;

-   wherein the composition is contained in a pressurized container is    substantially flowable and provides a breakable foam upon release,    which is thermally stable, yet breaks under sheer force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In an embodiment there is provided a foamable oil in water nano emulsioncomposition wherein the viscosity is selected from the group consistingof (1) between about 6000 cP and about 4000 cP (2) between about 4000 cPand about 2000 cP (3) between about 2000 cP and about 500 cP (4) betweenabout 500 cP and about 1 cP.

In an embodiment the viscosity is preferably between about 500 cP andabout 1 cP and the foam is of good or excellent quality.

In another embodiment the viscosity is above 20,000 cP.

In another embodiment the polymeric agent is a carbomer. In anotherembodiment the carbomer is the sole polymeric agent.

In a further embodiment the carbomer substantially contributes to theviscosity and exhibits resistant to viscosity reduction on nanoprocessing

In a further embodiment there is provided a foamable oil in water nanoemulsion composition comprising:

-   -   (a) A nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent comprising a carbomer polymeric agent, and a second        stabilizing agent selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent;    -   (c) water; and    -   (d) a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging    and wherein the viscosity of the pre foam formulation remains    substantially high after it has been subject to nano processing;

-   wherein the composition is contained in a pressurized container is    substantially flowable and provides a breakable foam upon release,    which is thermally stable, yet breaks under sheer force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In a still further embodiment there is provided a foamable oil in waternano emulsion composition comprising:

-   -   (a) a nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent, selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent; and    -   (c) water;

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging;

-   wherein the composition prior to addition of propellant is    translucent with a blue tint;

-   wherein if the composition is contained in a pressurized container    and further comprises a liquefied hydrocarbon gas propellant at a    concentration of about 3% to about 35% by weight of the total    composition it is substantially flowable and provides a breakable    foam upon release, which is thermally stable, yet breaks under sheer    force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In another embodiment there is provided a method of treating,alleviating or preventing a disorder of the skin, body cavity or mucosalsurface, wherein said disorder involves insufficient hydration of skinor a mucosal surface as one of its etiological factors, comprising:

-   -   administering topically to a subject having said disorder, a        foamed composition comprising:    -   (a) a nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent, selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent;    -   (c) water; and    -   (d) a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging;

-   wherein the composition is contained in a pressurized container is    substantially flowable and provides a breakable foam upon release,    which is thermally stable, yet breaks under sheer force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In an additional embodiment the composition further comprises an activeagent effective to treat a disorder and wherein the disorder is selectedfrom the group consisting of a vaginal disorder, a vulvar disorder, ananal disorder, a disorder of a body cavity, an ear disorder, a disorderof the nose, a disorder of the respiratory system, a bacterialinfection, fungal infection, viral infection, dermatosis, dermatitis,parasitic infections, disorders of hair follicles and sebaceous glands,scaling papular diseases, benign tumors, malignant tumors, reactions tosunlight, bullous diseases, pigmentation disorders, disorders ofcornification, pressure sores, disorders of sweating, inflammatoryreactions, xerosis, ichthyosis, allergy, burn, wound, cut, chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, osteoarthritis, joint pain, hormonal disorder,pelvic inflammation, endometritis, salpingitis, oophoritis, genitalcancer, cancer of the cervix, cancer of the vulva, cancer of the vagina,vaginal dryness, dyspareunia, anal and rectal disease, analabscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease,hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation,polyps of the colon and rectum.

In one or more embodiments there is provided a method of promoting thepenetration of an active agent into the surface layers of the skin andmucosal membranes, comprising: apply a foamable composition to thesurface layers of a stem or mucosal membrane, the foamable compositioncomprising:

-   -   (a) a nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent, selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent;    -   (c) water; and    -   (d) a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging;

-   wherein the composition is contained in a pressurized container is    substantially flowable and provides a breakable foam upon release,    which is thermally stable, yet breaks under sheer force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In a further embodiment of the method of promoting penetration theactive agent is selected from the group consisting of an anti-infective,an antibiotic, an antibacterial agent, an antifungal agent, an antiviralagent, an antiparasitic agent, an steroidal antiinflammatory agent, animmunosuppressive agent, an immunomodulator, an immunoregulating agent,a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, avitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, avitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, avitamin F derivative, vitamin K, a vitamin K derivative, a wound healingagent, a disinfectant, an anesthetic, an antiallergic agent, an alphahydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, aprotein, a peptide, a neuropeptide, a allergen, an immunogenicsubstance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylicacid, azelaic acid, sebacic acid, adipic acid, fumaric acid, a retinoid,an antiproliferative agent, an anticancer agent, a photodynamic therapyagent, an anti-wrinkle agent, a radical scavenger, a metal oxide (e.g.,titanium dioxide, zinc oxide, zirconium oxide, iron oxide), siliconeoxide, an anti wrinkle agent, a skin whitening agent, a skin protectiveagent, a masking agent, an anti-wart agent and a refatting agent.

In a further embodiment there is provided a method of treating,alleviating or preventing a disorder of the skin, body cavity or mucosalsurface, wherein said disorder involves insufficient hydration of skinor a mucosal surface as one of its etiological factors, comprising:

-   -   administering topically to a subject having said disorder, a        foamed composition comprising:    -   (a) a nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent, selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent; and    -   (c) water;

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging;

-   wherein the composition prior to addition of propellant is    translucent with a blue tint;

-   wherein if the composition is contained in a pressurized container    and further comprises a liquefied hydrocarbon gas propellant at a    concentration of about 3% to about 35% by weight of the total    composition it is substantially flowable and provides a breakable    foam upon release, which is thermally stable, yet breaks under sheer    force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In a further embodiment of the method of treating, alleviating orpreventing a disorder of the skin, body cavity or mucosal surface thecomposition further comprises an active agent effective to treat adisorder and wherein the disorder is selected from the group describedabove.

In a further embodiment there is provided a method of promoting thepenetration of an active agent into the surface layers of the skin andmucosal membranes, comprising: apply a foamable composition to thesurface layers of a stem or mucosal membrane, the foamable compositioncomprising:

-   -   (a) a nano oil globule system, comprising substantially of        sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent, selected from the group consisting of        -   i. a non-ionic surfactant,        -   ii. an ionic surfactant, and        -   iii. a polymeric agent; and    -   (c) water;

-   wherein the oil, stabilizer and water are selected to provide a    composition that is substantially homogenous and resistant to aging;

-   wherein the composition prior to addition of propellant is    translucent with a blue tint;

-   wherein if the composition is contained in a pressurized container    and further comprises a liquefied hydrocarbon gas propellant at a    concentration of about 3% to about 35% by weight of the total    composition it is substantially flowable and provides a breakable    foam upon release, which is thermally stable, yet breaks under sheer    force; and

-   wherein the bubble size of the resultant foam is significantly    greater than the bubble size of the resultant foam from a    composition with the same ingredients which has not been subject to    nano processing.

In a further embodiment of the method of promoting the penetration of anactive agent the active agent is selected from the group listed above.

In one or more other embodiments there is provided a foamable oil inwater nano emulsion composition for use as a medicament or in themanufacture of a medicament.

In one or more embodiments there is also provided a method of producinga foam having improved foam bubble size comprising

-   -   i. preparing a pre foam oil in water emulsion formulation;    -   ii. subjecting the pre foam formulation to high pressure        mechanical stress to produce a nano emulsion;    -   iii. storing the nano emulsion in a sealed pressurized container        that further comprises a liquefied hydrocarbon gas propellant at        a concentration of about 3% to about 25% by weight of the total        composition and having an outlet capable of releasing the        pressurized product as a foam; and    -   iv. releasing the foam;        -   wherein the bubble size of the resultant foam is            significantly greater than the bubble size of a resultant            foam from the pre foam oil in water emulsion formulation            stored in a sealed pressurized container that further            comprises a liquefied hydrocarbon gas propellant at a            concentration of about 3% to about 25% by weight of the            total composition and having an outlet capable of releasing            the pressurized product as a foam.

The foamable oil in water nano emulsion composition includes:

-   -   (a) an oil globule system selected from the group consisting of        oil bodies and sub-micron oil globules;    -   (b) about 0.1% to about 5% by weight of at least one stabilizing        agent selected from the group consisting of a non-ionic        surfactant selected from the group consisting of a non-ionic        surfactant, having an HLB value between 9 and 16, an ionic        surfactant; and a polymeric agent; and    -   (c) a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.

Water and optional ingredients are added to complete the total mass to100%. Upon release from an aerosol container, the foamable compositionforms an expanded foam suitable for topical administration.

In one or more embodiments, the oil globules are oil bodies. Oil bodies,also termed “oleosomes”, “lipid bodies” and “spherosomes”, are smalldiscrete oleaginous particles, ranging in size from about 1 to about 3μm along one dimension. Oil bodies consist of triacylglycerols (TAG)surrounded by phospholipids (PL) and alkaline proteins, termed oleosins.

Triacylglycerides (also termed triglycerides) are chemically defined asglycerol esters of fatty acids. The seed oil present in the oil bodyfraction of plant species is a mixture of various triacylglycerides, ofwhich the exact composition depends on the plant species from which theoil is derived.

Phospolipids possess a structure that is very similar to that of thetriacylglycerides except that a terminal carbon of the glycerol backboneis esterified to phosphoric acid. Substitution of the hydrogen atom ofphosphatidic acid results in additional phospholipids classes, includingbut not limited to the following:

Substitution Phospholipid Ethanolamine Phosphatidylethanolamine CholinePhosphatidylcholine, also called lecithins Serine PhosphatidylserineGlycerol Phosphatidylglycerol Myo-inositol Phosphatidylinositol

Oleosins are highly lipophilic small proteins of about 15 to 26 kD. Theyare expressed at high levels in many seeds and are specifically targetedto oil-bodies. Oleosins completely cover the surface of the subcellularoil bodies.

Oil-bodies are abundant in plant seeds and are among the simplestorganelles present in eukaryotes. They are remarkably stable both insidethe cells and in isolated preparations.

Oil bodies are prepared from plant seeds. Exemplary plant seeds include(alphabetically) almond (Prunus dulcis); anise (Pimpinella anisum);avocado (Persea spp.); beach nut (Fagus sylvatica); borage (also knownas evening primrose) (Boragio officinalis); Brazil nut (Bertholletiaexcelsa); candle nut (Aleuritis tiglium); carapa (Carapa guineensis);cashew nut (Ancardium occidentale); castor (Ricinus communis); coconut(Cocus nucifera); coriander (Coriandrum sativum); cottonseed (Gossypiumspp.); crambe (Crambe abyssinica); Crepis alpina; croton (Crotontiglium); Cuphea spp.; dill (Anethum gravealis); Euphorbia lagascae;Dimorphoteca pluvialis; false flax (Camolina sativa); fennel (Foeniculumvulgaris); groundnut (Arachis hypogaea); hazelnut (coryllus avellana);hemp (Cannabis sativa); honesty plant (Lunnaria annua); jojoba(Simmiondsia chinensis); kapok fruit (Ceiba pentandra); kukui nut(Aleuritis moluccana); Lesquerella spp., linseed/flax (Linumusitatissimum); macademia nut (Macademia spp.); maize (Zea mays); meadowfoam (Limnanthes alba); mustard (Brassica spp. and Sinapis alba); oilpalm (Elaeis guineeis); oiticia (Licania rigida); paw paw (Assiminatriloba); pecan (Juglandaceae spp.); perilla (Perilla frutescens);physic nut (Gairopha curcas); pilinut (Canariuim ovatum); pine nut (pinespp.); pistachio (Pistachia vera); pongam (Bongamin glabra); poppy seed(Papaver soniferum); rapeseed (Brassica spp.); safflower (Carthamustinctorius); sesame seed (Sesamum indicum); soybean (Glycine max);squash (Cucurbita maxima); sal tree (Shorea rubusha); Stokes aster(Stokesia laevis); sunflower (Helianthus annuus); tukuma (Astocaryaspp.); tung nut (Aleuritis cordata); and vernolnia (Verzoniagalamensis). Isolation of oil bodies from plant sources is well known.See, for example, U.S. Pat. No. 5,650,554.

Stable artificial oil bodies can be reconstituted with triacylglycerol,phospholipid, and oleosin via sonication, as described, for example inJ. T. C. Tzen, Y. Z. Cao, P. Laurent, C. Ratnayake, and A. H. C. Huang.1993. Lipids, proteins, and structure of seed oil bodies from diversespecies. Plant Physiol. 101:267-276.

The skin-beneficial effects of oil bodies include, but are not limitedto (1) antioxidant effects (resulting from the presence of tocopheroland other antioxidants naturally present in the oil bodies); (2)occlusivity, as determined by improved skin barrier function and reducedtrans-epidermal water loss; and (3) emolliency. Furthermore, the oilbodies building blocks—the triacylglycerides and thephospholipids—contain unsaturated or polyunsaturated fatty acids.Exemplary unsaturated fatty acids are omega-3 and omega-6 fatty acids.Other examples of such polyunsaturated fatty acids are linoleic andlinolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA)and docosahexaenoic acid (DHA). Such unsaturated fatty acids are knownfor their skin-conditioning and anti-inflammatory effects, whichcontribute to the therapeutic benefit of the present foamablecomposition.

Because oil bodies contain phospholipids and oleosins, whichconcurrently carry hydrophobic and hydrophilic moieties, they act asemulsifiers and, as a result, upon dilution with water with mild mixing,they spontaneously form an emulsion.

In one or more embodiments, the oil globules are sub-micron oilglobules, i.e., oil globules, which have a number-average size of lessthan 1,000 nm. An emulsion, comprising sub-micron globules or nano-sizeglobules is called sub-micron emulsion (“SME”) or microemulsion ornanoemulsion, respectively. In one or more embodiments, the oil globuleshave a number-average size of less than 500 nm; or less than 200 nm; orless than 100 nm. In certain embodiments, the oil globules havenumber-average size in the following ranges: (i) 40 nm to 1,000 nm. (ii)40 nm to 500 nm; (iii) 40 nm to 200 nm; or (iv) 40 nm to 100 nm.

SMEs are dispersions of oil and water. With reference to conventionalemulsions, SMEs are more stable, making them a favorable vehicle forpharmaceutical compositions, which have to maintain stability for longperiods of time. SMEs may be used in vehicles for transportingnutraceuticals, medicaments, peptides or proteins. The decrease in sizeof the globules makes it possible to promote the penetration of theactive agents into the surface layers of the skin and mucosal membranes.

In SMEs, the active compounds can be solubilized. The general concept ofsolubilization of active components and its utilization may be found inthe following review articles: 1. Solans, C., Pons, R., Kunieda, H“Overview of basic aspects of microemulsions” Industrial Applications ofMicroemulsions, Solans, C., Kunieda, H., Eds. Dekker, New York (1997);66: 1-17, 2. Dungan, S. R., “Microemulsions in foods: properties andapplication” ibid 148-170; 3. Holmberg, K. “Quarter century progress andnew horizons in microemulsions” in Micelles, Microemulsions andMonolayers, Shah, O. Ed.; Dekker: New York (1998) 161-192; 4. Garti, N.“Microemulsions, emulsions, double emulsions and emulsions in food” inFormulation Science (proceeding from formulation forum '97 associationof formulation chemists) (1998) 1, 147-219; 5. Ezrahi, S., Aserin, A.Garti, N. in Micoremulsions-fundamental wad applied aspects Kumar, P.and Mittal, K. L. Eds. Marcel Dekker, Inc. New York (1999) “Aggregationbehavior in one-phase (Winsor IV) systems” 185-246; 6. Garti, N.Clement, V., Leser, M., Aserin, A. Fanun, M. “Sucrose estersmicroemulsions J. Molec. Liquids (1999) 80, 253-296.

In certain embodiments, the production of SMEs and nanoemulsion involvesvery-high sheer homogenizers. An exemplary homogenizer, suitable forproducing nano-emulsions is the commercially-available“Microfluidizer®”. Microfluidizer® fluid processors are built fordeagglomeration and dispersion of uniform submicron particles andcreation of stable emulsions and dispersions. Microfluidizer processorsovercome limitations of conventional processing technologies byutilizing high-pressure streams that collide at ultra-high velocities inprecisely defined microchannels. Combined forces of shear and impact actupon products to attain uniform particle and droplet size reduction(often submicron), deagglomeration and high yield cell disruption.

Notwithstanding the above, any other very-high sheer homogenizer,capable of producing submicron particles is suitable for use in theproduction of a microemulsions or a nanoemulsion according to thepresent invention.

In additional embodiments, the SMEs form spontaneously with gentlemixing such as hand shaking.

The sub-micron particles contain at least one organic carrier,preferably a hydrophobic organic carrier. In addition, the compositionmay contain one or more of a hydrophobic organic carrier, a polarsolvent, an emollient and mixtures thereof, at a concentration of about2% to about 5%, or about 5% to about 10%, or about 10% to about 20%, orabout 20% to about 50% by weight.

A “hydrophobic organic carrier” as used herein refers to a materialhaving solubility in distilled water at ambient temperature of less thanabout 1 gm per 100 mL, more preferable less than about 0.5 gm per 100mL, and most preferably less than about 0.1 gm per 100 mL. It is liquidat ambient temperature. The identification of a hydrophobic organiccarrier or “hydrophobic solvent”, as used herein, is not intended tocharacterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a hydrophobic carrier inthe foamable compositions described herein.

In one or more embodiments, the hydrophobic organic carrier is an oil,such as mineral oil. Mineral oil (Chemical Abstracts Service Registrynumber 8012-95-1) is a mixture of aliphatic, naphthalenic, and aromaticliquid hydrocarbons that derive from petroleum. It is typically liquid;its viscosity is in the range of between about 35 CST and about 100 CST(at 40° C.), and its pour point (the lowest temperature at which an oilcan be handled without excessive amounts of wax crystals forming sopreventing flow) is below 0° C. In one or more embodiments, the termhydrophobic organic carrier does not include thick or semi-solidmaterials, such as white petrolatum, also termed “Vaseline”, which, incertain compositions is disadvantageous due to its waxy nature andsemi-solid texture.

According to one or more embodiments, hydrophobic solvents are liquidoils originating from vegetable, marine or animal sources. Suitableliquid oil includes saturated, unsaturated or polyunsaturated oils. Byway of example, the unsaturated oil may be olive oil, corn oil, soybeanoil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil,borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil,cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, eveningprimrose oils or mixtures thereof, in any proportion.

Suitable hydrophobic solvents also include polyunsaturated oilscontaining poly-unsaturated fatty acids. In one or more embodiments,said unsaturated fatty acids are selected from the group of omega-3 andomega-6 fatty acids. Examples of such polyunsaturated fatty acids arelinoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA). Such unsaturated fatty acidsare known for their skin-conditioning effect, which contribute to thetherapeutic benefit of the present foamable composition. Thus, thehydrophobic solvent can include at least 6% of an oil selected fromomega-3 oil, omega-6 oil, and mixtures thereof. In the context of thepresent invention, oils that possess therapeutically beneficialproperties are termed “therapeutically active oil.”

Another class of hydrophobic solvents is the essential oils, which arealso considered therapeutically active oil, which contain activebiologically occurring molecules and, upon topical application, exert atherapeutic effect, which is conceivably synergistic to the beneficialeffect of the NSAID in the composition.

Another class of therapeutically active oils includes liquid hydrophobicplant-derived oils, which are known to possess therapeutic benefits whenapplied topically.

Silicone oils also may be used and are desirable due to their known skinprotective and occlusive properties. Suitable silicone oils includenon-volatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. These are chosenfrom cyclic or linear polydimethylsiloxanes containing from about 3 toabout 9, preferably from about 4 to about 5, silicon atoms. Volatilesilicones such as cyclomethicones can also be used. Silicone oils arealso considered therapeutically active oil, due to their barrierretaining and protective properties.

The organic carrier may be a mixture of two or more of the abovehydrophobic solvents in any proportion.

A further class of organic carriers includes “emollients” that have asoftening or soothing effect, especially when applied to body areas,such as the skin and mucosal surfaces. Emollients are not necessarilyhydrophobic. Examples of suitable emollients include hexyleneglycol,propylene glycol, isostearic acid derivatives, isopropyl palmitate,isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate,maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, acetylated oil bodies alcohol, cetyl acetate, phenyltrimethicone, glyceryl oleate, tocopheryl linoleate, wheat germglycerides, arachidyl propionate, myristyl lactate, decyl oleate,propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityltetrastearate, neopentylglycol dicaprylate/dicaprate, isononylisononanoate, isotridecyl isononanoate, myristyl myristate, triisocetylcitrate, octyl dodecanol, sucrose esters of fatty acids, octylhydroxystearate and mixtures thereof.

According to one or more embodiments of the present invention, theorganic carrier includes a mixture of a hydrophobic solvent and anemollient. According to one or more embodiments, the foamablecomposition is a mixture of mineral oil and an emollient in a ratiobetween 2:8 and 8:2 on a weight basis.

A “polar solvent” is an organic solvent, typically soluble in both waterand oil. Examples of polar solvents include polyols, such as glycerol(glycerin), propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol,other glycols, sulfoxides, such as dimethylsulfoxide (DMSO),dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxideunits), azone (1-dodecylazacycloheptan-2-one),2-(n-nonyl)-1,3-dioxolane, esters, such as isopropylmyristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate,capric/caprylic triglycerides, octylmyristate, dodecyl-myristate;myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketones;amides, such as acetamide oleates such as triolein; various alkanoicacids such as caprylic acid; lactam compounds, such as azone; alkanols,such as dialkylamino acetates, and admixtures thereof.

According to one or more embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200(MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

According to one or more embodiments, the foamable composition issubstantially alcohol-free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butanol, iso-butanol, t-butanol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. Thus, the composition is substantially alcohol-free and includesless than about 5% final concentration of lower alcohols, preferablyless than about 2%, more preferably less than about 1%.

The composition includes a stabilizing agent, which may be a polymericagent. The polymeric agent serves to stabilize the foam composition andto control drug residence in the target organ. Exemplary polymericagents are classified below in a non-limiting manner. In certain cases,a given polymer can belong to more than one of the classes providedbelow.

The polymeric agent may be a gelling agent. A gelling agent controls theresidence of a therapeutic composition in the target site of treatmentby increasing the viscosity of the composition, thereby limiting therate of its clearance from the site. Many gelling agents are known inthe art to possess mucoadhesive properties.

The gelling agent can be a natural gelling agent, a synthetic gellingagent and an inorganic gelling agent. Exemplary gelling agents that canbe used in accordance with one or more embodiments of the presentinvention include, for example, microcrystalline cellulose, Aculyn aHydrophobically-modified Ethoxylated Urethane, naturally-occurringpolymeric materials, such as locust bean gum, sodium alginate, sodiumcaseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate,xanthan gum, quince seed extract, tragacanth gum, guar gum, starch,chemically modified starches and the like, semi-synthetic polymericmaterials such as cellulose ethers (e.g. hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose),guar gum, hydroxypropyl guar gum, soluble starch, cationic celluloses,cationic guars, and the like, and synthetic polymeric materials, such ascarboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol,polyacrylic acid polymers, polymethacrylic acid polymers, polyvinylacetate polymers, polyvinyl chloride polymers, polyvinylidene chloridepolymers and the like. Mixtures of the above compounds are contemplated.

Further exemplary gelling agents include the acrylic acid/ethyl acrylatecopolymers and the carboxyvinyl polymers sold, for example, by the B.F.Goodrich Company under the trademark of Carbopol® resins. These resinsconsist essentially of a colloidal water-soluble polyalkenyl polyethercrosslinked polymer of acrylic acid crosslinked with from 0.75% to 2% ofa crosslinking agent such as polyallyl sucrose or polyallylpentaerythritol. Examples include Carbopol® 934, Carbopol® 940,Carbopol® 950, Carbopol® 980, Carbopol® 951 and Carbopol® 981. Carbopol®934 is a water-soluble polymer of acrylic acid crosslinked with about 1%of a polyallyl ether of sucrose having an average of about 5.8 allylgroups for each sucrose molecule.

The gelling agent may be a water-soluble cellulose ether. Preferably,the water-soluble cellulose ether is selected from the group consistingof methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose (Methocel), hydroxyethyl cellulose,methylhydroxyethylcellulose, methylhydroxypropylcellulose,hydroxyethylcarboxymethylcellulose, carboxymethylcellulose andcarboxymethylhydroxyethylcellulose. More preferably, the water-solublecellulose ether is selected from the group consisting ofmethylcellulose, hydroxypropyl cellulose and hydroxypropylmethylcellulose (Methocel). In one or more embodiments, the compositionincludes a combination of a water-soluble cellulose ether; and anaturally-occurring polymeric materials, selected from the groupincluding xanthan gum, guar gum, carrageenan gum, locust bean gum andtragacanth gum.

Yet, in other embodiments, the gelling agent includes inorganic gellingagents, such as silicone dioxide (fumed silica).

The polymeric agent may be a mucoadhesive agent.Mucoadhesion/bioadhesion is defined as the attachment of synthetic orbiological macromolecules to a biological tissue. Mucoadhesive agentsare a class of polymeric biomaterials that exhibit the basiccharacteristic of a hydrogel, i.e. swell by absorbing water andinteracting by means of adhesion with the mucous that covers epithelia.Compositions of the present invention may contain a mucoadhesivemacromolecule or polymer in an amount sufficient to confer bioadhesiveproperties. The bioadhesive macromolecule enhances the delivery ofbiologically active agents on or through the target surface. Themucoadhesive macromolecule may be selected from acidic syntheticpolymers, preferably having at least one acidic group per four repeatingor monomeric subunit moieties, such as poly(acrylic)- and/orpoly(methacrylic) acid (e.g., Carbopol®, Carbomer®), poly(methylvinylether/maleic anhydride) copolymer, and their mixtures and copolymers;acidic synthetically modified natural polymers, such ascarboxymethylcellulose (CMC); neutral synthetically modified naturalpolymers, such as (hydroxypropyl)methylcellulose; basic amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth,and karaya gum; and neutral synthetic polymers, such as polyvinylalcohol or their mixtures. An additional group of mucoadhesive polymersincludes natural and chemically modified cyclodextrin, especiallyhydroxypropyl-β-cyclodextrin. Such polymers may be present as freeacids, bases, or salts, usually in a final concentration of about 0.01%to about 0.5% by weight.

A suitable bioadhesive macromolecule is the family of acrylic acidpolymers and copolymers, (e.g., Carbopol®). These polymers contain thegeneral structure —[CH₂—CH(COOH)—]_(n). Hyaluronic acid and otherbiologically-derived polymers may be used.

Exemplary bioadhesive or mucoadhesive macromolecules have a molecularweight of at least 50 kDa, or at least 300 kDa, or at least 1,000 kDa.Favored polymeric ionizable macromolecules have not less than 2 molepercent acidic groups (e.g., COOH, SO3H) or basic groups (NH2, NRH,NR2), relative to the number of monomeric units. The acidic or basicgroups can constitute at least 5 mole percent, or at least 10 molepercent, or at least 25, at least 50 mole percent, or even up to 100mole percent relative to the number of monomeric units of themacromolecule.

Yet, another group of mucoadhesive agent includes inorganic gellingagents such as silicon dioxide (fumed silica), including but not limitedto, AEROSIL 200 (DEGUSSA).

Many mucoadhesive agents are known in the art to also possess gellingproperties.

The polymeric agent may be a film forming component. The film formingcomponent may include at least one water-insoluble alkyl cellulose orhydroxyalkyl cellulose. Exemplary alkyl cellulose or hydroxyalkylcellulose polymers include ethyl cellulose, propyl cellulose, butylcellulose, cellulose acetate, hydroxypropyl cellulose, hydroxybutylcellulose, and ethylhydroxyethyl cellulose, alone or in combination. Inaddition, a plasticizer or a cross linking agent may be used to modifythe polymer's characteristics. For example, esters such as dibutyl ordiethyl phthalate, amides such as diethyldiphenyl urea, vegetable oils,fatty acids and alcohols such as oleic and myristyl acid may be used incombination with the cellulose derivative.

The polymeric agent may be a phase change polymer, which alters thecomposition behavior from fluid-like prior to administration tosolid-like upon contact with the target mucosal surface. Such phasechange results from external stimuli, such as changes in temperature orpH and exposure to specific ions (e.g., Ca²⁺). Non-limiting examples ofphase change polymers include poly(N-isopropylamide), Poloxamer 407® andSmart-Gel® (Poloxamer+PAA). The polymeric agent is present in an amountin the range of about 0.01% to about 5.0% by weight of the foamcomposition. In one or more embodiments, it is typically less than about1 wt % of the foamable composition.

Surface-Active Agent

The stabilizing agent may also be a surface-active agent. Surface-activeagents (also termed “surfactants”) include any agent linking oil andwater in the composition, in the form of emulsion. A surfactant'shydrophilic/lipophilic balance (HLB) describes the emulsifier's affinitytoward water or oil. HLB is defined for non-ionic surfactants. The HLBscale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic),with 10 representing an equal balance of both characteristics.Lipophilic emulsifiers form water-in-oil (w/o) emulsions; hydrophilicsurfactants form oil-in-water (o/w) emulsions. The HLB of a blend of twoemulsifiers equals the weight fraction of emulsifier A times its HLBvalue plus the weight fraction of emulsifier B times its HLB value(weighted average). In many cases a single surfactant may suffice. Inother cases a combination of two or more surfactants is desired.Reference to a surfactant in the specification can also apply to acombination of surfactants or a surfactant system. As will beappreciated by a person skilled in the art which surfactant orsurfactant system is more appropriate is related to the vehicle andintended purpose. In general terms a combination of surfactants isusually preferable where the vehicle is an emulsion. In an emulsionenvironment a combination of surfactants can be significant in producingbreakable forms of good quality. It has been further discovered that thegenerally thought considerations for HLB values for selecting asurfactant or surfactant combination are not always binding foremulsions and that good quality foams can be produced with a surfactantor surfactant combination both where the HLB values are in or towardsthe lipophilic side of the scale and where the HLB values are in ortowards the hydrophilic side of the scale. Surfactants also play a rolein foam formation where the foamable formulation is a single phasecomposition.

The relationship between oil and surfactant is indicated by the requiredpredicted HLB for the oil and the parallel theoretical HLB of thesurfactant as shown in the non limiting examples below.

According to one or more embodiments the composition contains a singlesurfactant having an HLB value between about 2 and 9, or more than onesurfactant and the weighted average of their HLB values is between about2 and about 9. Lower HLB values may in certain embodiments be moreapplicable to water in oil emulsions.

According to one or more embodiments the composition contains a singlesurfactant having an HLB value between about 7 and 14, or more than onesurfactant and the weighted average of their HLB values is between about7 and about 14. Mid range HLB values may in certain embodiments be moresuitable for oil in water nano emulsion s.

According to one or more other embodiments the composition contains asingle surfactant having an HLB value between about 9 and about 19, ormore than one surfactant and the weighted average of their HLB values isbetween about 9 and about 19. In a waterless or substantially waterlessenvironment a wide range of HLB values may be suitable.

Preferably, the composition of the present invention contains anon-ionic surfactant. Nonlimiting examples of possible non-ionicsurfactants include a polysorbate, polyoxyethylene (20) sorbitanmonostearate, polyoxyethylene (20) sorbitan monooleate, apolyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59;a polyoxyethylene alkyl ether, polyoxyethylene cetyl ether,polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether,polyethylene glycol cetyl ether, steareths such as steareth 2, brij 21,brij 721, brij 38, brij 52, brij 56 and brij W1, a sucrose ester, apartial ester of sorbitol and its anhydrides, sorbitan monolaurate,sorbitan monolaurate, a monoglyceride, a diglyceride, isoceteth-20 andmono-, di- and tri-esters of sucrose with fatty acids. In certainembodiments, suitable sucrose esters include those having high monoestercontent, which have higher HLB values.

In certain embodiments with wax as emollient, surfactants are selectedwhich can provide a close packed surfactant layer separating the oil andwater phases. To achieve such objectives combinations of at least twosurfactants are selected. Preferably, they should be complex emulgatorsand more preferably they should both be of a similar molecular type. Forexample, a pair of ethers like steareth 2 and steareth 21, or a pair ofesters for example, PEG-40 stearate and polysorbate 80. In certaincircumstances POE esters cannot be used and a combination of sorbitanlaurate and sorbitan stearate or a combination of sucrose stearic acidester mixtures and sodium laurate may be used. All these combinationsdue to their versatility and strength may also be used satisfactorilyand effectively with wax formulations, although the amounts andproportion may be varied according to the formulation and its objectivesas will be appreciated by a man of the art.

It has been discovered also that by using a derivatized hydrophilicpolymer with hydrophobic alkyl moieties as a polymeric emulsifier suchas pemulen it is possible to stabilize the emulsion better about or atthe region of phase reversal tension. Other types of derivatizedpolymers like silicone copolymers, derivatized starch [Aluminum StarchOctenylsuccinate (ASOS)]/[DRY-FLO AF Starch], and derivatized dexrin mayalso a similar stabilizing effect.

A series of dextrin derivative surfactants prepared by the reaction ofthe propylene glycol polyglucosides with a hydrophobicoxirane-containing material of the glycidyl ether are highlybiodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and SurfacesA: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15Jun. 2006, Pages 190-193].

Non-limiting examples of non-ionic surfactants that have HLB of about 7to about 12 include steareth 2 (HLB˜4.9); glyceryl monostearate/PEG 100stearate (Av HLB˜11.2); stearate Laureth 4 (HLB˜9.7) and cetomacrogolether (e.g., polyethylene glycol 1000 monocetyl ether).

Non-limiting examples of preferred surfactants, which have a HLB of 4-19are set out in the Table below:

Surfactant HLB steareth 2 ~4.9 glyceryl monostearate/PEG 100 stearateAv~11.2 Glyceryl Stearate ~4 Steareth-21 ~15.5 peg 40 stearate ~16.9polysorbate 80 ~15 sorbitan stearate ~4.7 laureth 4 ~9.7 Sorbitanmonooleate (span 80) ~4.3 ceteareth 20 ~15.7 steareth 20 ~15.3 Ceteth 20~15.7 Macrogol Cetostearyl Ether ~15.7 Ceteth 2 (Lipocol C-2) ~5.3PEG-30 Dipolyhydroxystearate ~5.5 sucrose distearate (Sisterna SP30) ~6polyoxyethylene (100) stearate ~18.8

In one or more embodiments the surfactant is a complex emulgator inwhich the combination of two or more surfactants can be more effectivethan a single surfactant and provides a more stable emulsion or improvedfoam quality than a single surfactant. For example and by way ofnon-limiting explanation it has been found that by choosing say twosurfactants, one hydrophobic and the other hydrophilic the combinationcan produce a more stable emulsion than a single surfactant. Preferably,the complex emulgator comprises a combination of surfactants whereinthere is a difference of about 4 or more units between the HLB values ofthe two surfactants or there is a significant difference in the chemicalnature or structure of the two or more surfactants.

Specific non limiting examples of surfactant systems are, combinationsof polyoxyethylene alkyl ethers, such as Brij 59/Brij10; Brij 52/Brij10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/Brij 721);combinations of polyoxyethylene stearates such as Myrj 52/Myrj 59;combinations of sucrose esters, such as Surphope 1816/Surphope 1807;combinations of sorbitan esters, such as Span 20/Span 80; Span 20/Span60; combinations of sucrose esters and sorbitan esters, such as Surphope1811 and Span 60; combinations of liquid polysorbate detergents and PEGcompounds, such as Tween 80/PEG-40 stearate; methyl glucasosequistearate; polymeric emulsifiers, such as Permulen (TRI or TR2);liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1),Nikomulese (41) and Montanov (68) and the like.

In certain embodiments the surfactant is preferably one or more of thefollowing: a combination of steareth-2 and steareth-21 on their own orin combination with glyceryl monostearate (GMS); in certain otherembodiments the surfactant is a combination of polysorbate 80 and PEG-40stearate. In certain other embodiments the surfactant is a combinationof glyceryl monostearate/PEG 100 stearate. In certain other embodimentsthe surfactant is a combination of two or more of stearate 21, PEG 40stearate, and polysorbate 80. In certain other embodiments thesurfactant is a combination of two or more of laureth 4, span80, andpolysorbate 80. In certain other embodiments the surfactant is acombination of two or more of GMS and ceteareth. In certain otherembodiments the surfactant is a combination of two or more of steareth21, ceteareth 20, ceteth 2 and laureth 4 In certain other embodimentsthe surfactant is a combination of ceteareth 20 and polysorbate 40stearate. In certain other embodiments the surfactant is a combinationof span 60 and GMS. In certain other embodiments the surfactant is acombination of two or all of PEG 40 stearate, sorbitan stearate andpolysorbate 60

In certain other embodiments the surfactant is one or more of sucrosestearic acid esters, sorbitan laureth, and sorbitan stearate.

Without being bound by any particular theory or mode of operation, it isbelieved that the use of non-ionic surfactants with significanthydrophobic and hydrophilic components, increase the emulsifier or foamstabilization characteristics of the composition. Similarly, withoutbeing bound by any particular theory or mode of operation, usingcombinations of surfactants with high and low HLB's to provide arelatively close packed surfactant layer may strengthen the emulsion.

In one or more embodiments the stability of the composition can beimproved when a combination of at least one non-ionic surfactant havingHLB of less than 9 and at least one non-ionic surfactant having HLB ofequal or more than 9 is employed. The ratio between the at least onenon-ionic surfactant having HLB of less than 9 and the at least onenon-ionic surfactant having HLB of equal or more than 9, is between 1:8and 8:1, or at a ratio of 4:1 to 1:4. The resultant HLB of such a blendof at least two emulsifiers is preferably between about 9 and about 14.

Thus, in an exemplary embodiment, a combination of at least onenon-ionic surfactant having HLB of less than 9 and at least onenon-ionic surfactant having HLB of equal or more than 9 is employed, ata ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein theHLB of the combination of emulsifiers is preferably between about 5 andabout 18.

In certain cases, the surfactant is selected from the group of cationic,zwitterionic, amphoteric and ampholytic surfactants, such as sodiummethyl cocoyl taurate, sodium methyl oleoyl taurate, sodium laurylsulfate, triethanolamine lauryl sulfate and betaines.

Many amphiphilic molecules can show lyotropic liquid-crystalline phasesequences depending on the volume balances between the hydrophilic partand hydrophobic part. These structures are formed through themicro-phase segregation of the two parts. Many amphiphilic molecules canshow lyotropic liquid-crystalline phase sequences depending on thevolume balances between the hydrophilic part and hydrophobic part. Thesestructures are formed through the micro-phase segregation of twoincompatible components on a nanometer scale. Soap is an everydayexample of a lyotropic liquid crystal. Certain types of surfactants tendto form lyotropic liquid crystals in emulsions interface (oil-in-water)and exert a stabilizing effect

In one or more embodiments the surfactant is a surfactant or surfactantcombination is capable of or which tends to form liquid crystals.Surfactants which tend to form liquid crystals may improve the qualityof foams. Non limiting examples of surfactants with postulated tendencyto form interfacial liquid crystals are: phospholipids, alkylglucosides, sucrose esters, sorbitan esters.

In one or more embodiments the at least one surfactant is liquid.

In one or more embodiments the liquid surfactant is a polysorbate,preferably polysorbate 80 or 60.

In one or more embodiments the at least one surfactant is solid, semisolid or waxy.

It should be noted that HLB values may not be so applicable to non ionicsurfactants, for example, with liquid crystals or with silicones. AlsoHLB values may be of lesser significance in a waterless or substantiallynon-aqueous environment.

In one or more embodiments the surfactant can be, a surfactant systemcomprising of a surfactant and a co surfactant, a waxy emulsifier, aliquid crystal emulsifier, an emulsifier which is solid or semi solid atroom temperature and pressure, or combinations of two or more agents inan appropriate proportion as will be appreciated a person skilled in theart. Where a solid or semi solid emulsifier combination is used it canalso comprise a solid or semi solid emulsifier and a liquid emulsifier.

In one or more embodiments of the present invention, the surface-activeagent includes at least one non-ionic surfactant. Ionic surfactants areknown to be irritants. Therefore, non-ionic surfactants are preferred inapplications including sensitive tissue such as found in most mucosaltissues, especially when they are infected or inflamed. Non-ionicsurfactants alone can provide formulations and foams of good orexcellent quality in the carriers and compositions of the presentinvention.

Thus, in a preferred embodiment, the surfactant, the compositioncontains a non-ionic surfactant. In another preferred embodiment thecomposition includes a mixture of non-ionic surfactants as the solesurfactant. Yet, in additional embodiments, the foamable compositionincludes a mixture of at least one non-ionic surfactant and at least oneionic surfactant in a ratio in the range of about 100:1 to 6:1. In oneor more embodiments, the non-ionic to ionic surfactant ratio is greaterthan about 6:1, or greater than about 8:1; or greater than about 14:1,or greater than about 16:1, or greater than about 20:1. In furtherembodiments, surfactant comprises a combination of a non-ionicsurfactant and an ionic surfactant, at a ratio of between 1:1 and 20:1

In one or more embodiments of the present invention, a combination of anon-ionic surfactant and an ionic surfactant (such as sodium laurylsulphate and cocamidopropylbetaine) is employed, at a ratio of between1:1 and 20:1, or at a ratio of 4:1 to 10:1; for example, about 1:1,about 4:1, about 8:1, about 12:1, about 16:1and about 20:1 or at a ratioof 4:1 to 10:1, for example, about 4:1, about 6:1, about 8:1 and about10:1.

In selecting a suitable surfactant or combination thereof it should beborne in mind that the upper amount of surfactant that may be used maybe limited by the shakability of the composition. If the surfactant isnon liquid, it can make the formulation to viscous or solid. This can beparticularly significant if the formulation has high molecular weight,e.g., a high molecular weight PEG or polymeric agents or petroleum or ifthe surfactants are large. Solvents and polymeric agents which have highmolecular weight and are very viscous or solid or waxy (e.g., Peg 1500,2000, etc. or petrolatum) can exacerbate the effect of a waxy or solidsurfactant on shakability or flowability In general terms, as the amountof non-liquid surfactant is increased the shakability of the formulationreduces until a limitation point is reached where the formulationbecomes non shakable and unsuitable. Thus in one embodiment, aneffective amount of surfactant may be used provided the formulationremains shakable. In other certain exceptional embodiments the upperlimit may be determined by flowability such as in circumstances wherethe composition is marginally or apparently non-shakable. Theformulation is sufficiently flowable to be able to flow through anactuator valve and be released and still expand to form a good qualityfoam.

In certain embodiments of the present invention the amount of surfactantor combination of surfactants is between about 0.05% to about 20%;between about 0.05% to about 15%. or between about 0.05% to about 10%.In a preferred embodiment the concentration of surfactant is betweenabout 0.2% and about 8%. In a more preferred embodiment theconcentration of surfactant is between about 1% and about 6%. In one ormore preferred embodiments the surfactant oil ratio is relatively highranging from about of the order of 1:1 to about 1: 10. Neverthelesslower levels are possible.

In some embodiments, it is desirable that the surfactant does notcontain a polyoxyethylene (POE) moiety, such as polysorbate surfactants,POE fatty acid esters, and POE alkyl ethers, because the active agent isincompatible with such surfactants. For example, the active agentpimecrolimus is not stable the presence of POE moieties, yet benefitsgreatly from the use of dicarboxylic esters as penetration enhancers. Insuch cases, alternative surfactants are employed. In an exemplarymanner, POE—free surfactants include non-ethoxylated sorbitan esters,such as sorbitan monopalmitate, sorbitan monostearate, sorbitantristearate, sorbitan monooleate, sorbitan trioleate, sorbitanmonolaurate and sorbitan sesquioleate; glycerol fatty acid esters, suchas glycerol monostearate and glycerol monooleate; mono-, di- andtri-esters of sucrose with fatty acids (sucrose esters), sucrosestearate, sucrose distearate sucrose palmitate and sucrose laurate; andalkyl polyglycosides, such as lauryl diglucoside.

If the composition as formulated is a substantially non shakablecomposition it is nevertheless possible as an exception in the scope ofthe present invention for the formulation to be flowable to a sufficientdegree to be able to flow through an actuator valve and be released andstill expand to form a good quality foam. This surprising and unusualexception may be due one or more of a number of factors such as the highviscosity, the softness, the lack of crystals, the pseudoplastic or semipseudo plastic nature of the composition and the dissolution of thepropellant into the composition. The propellant can change a merelyflowable composition into a shakable one.

In one or more embodiments of the present invention, the surface-activeagent includes mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), prepared from sucrose and esters of fatty acids or byextraction from sucro-glycerides. Suitable sucrose esters include thosehaving high monoester content, which have higher HLB values.

The surface-active agent is selected from anionic, cationic, nonionic,zwitterionic, amphoteric and ampholytic surfactants, as well as mixturesof these surfactants.

In the case wherein the oil globules are oil bodies, the surfactant canbe the phospholipids or the oil bodies.

Combination of surfactants are contemplated. In regular emulsioncompositions the total surfactant is usually in the range of about 0.1to about 5% of the foamable composition, and is typically less thanabout 2% or less than about 1%. However in order to form nano emulsionsit may be appropriate to use higher levels of surfactant, particularlyif nanoemulsions are desired with a diameter size in the range of aboutless than 500 nanometers. Thus, the total surfactant may be in the rangeof about 5% to about 25% and may preferably be in the range of about 6%to about 12%. In another preferred embodiment the total is about 8%.

In one or more embodiments the surfactant plays a role in thedetermination of the viscosity of the formulation. In particular withoutbeing bound by any theory the surfactants may have an inherent role inthe surprising loss or reduction of viscosity to less than 500 cP eventhough the viscosity of the formulation can be much higher prior to nanoprocessing with say up to six cycles with a high pressure homogenizer.

Substantially Alcohol-Free

According to one or more embodiments, the foamable composition issubstantially alcohol-free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butaneol, iso-butaneol, t-butaneol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. Thus, the composition is substantially alcohol-free and includesless than about 5% final concentration of lower alcohols, preferablyless than about 2%, more preferably less than about 1%.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. In some very limited casespossibly aided by the presence of silicone it may exceptionally bepossible to have a foamable composition which is flowable but notapparently shakable.

Breakability

A breakable foam is one that is thermally stable, yet breaks under sheerforce.

The breakable foam of the present invention is not “quick breaking”,i.e., it does not readily collapse upon exposure to body temperatureenvironment. Sheer-force breakability of the foam is clearlyadvantageous over thermally induced breakability, since it allowscomfortable application and well directed administration to the targetarea.

Preferably, foam adjuvant is included in the foamable compositions ofthe present invention to increase the foaming capacity of surfactantsand/or to stabilize the foam. In one or more embodiments of the presentinvention, the foam adjuvant agent includes fatty alcohols having 15 ormore carbons in their carbon chain, such as cetyl alcohol and stearylalcohol (or mixtures thereof). Other examples of fatty alcohols arearachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), aswell as alcohols with longer carbon chains (up to C50). Fatty alcohols,derived from beeswax and including a mixture of alcohols, a majority ofwhich has at least 20 carbon atoms in their carbon chain, are especiallywell suited as foam adjuvant agents. The amount of the fatty alcoholrequired to support the foam system is inversely related to the lengthof its carbon chains. Foam adjuvants, as defined herein are also usefulin facilitating improved spreadability and absorption of thecomposition.

In one or more embodiments of the present invention, the foam adjuvantagent includes fatty acids having 16 or more carbons in their carbonchain, such as hexadecanoic acid (C16) stearic acid (C18), arachidicacid (C20), behenic acid (C22), octacosanoic acid (C28), as well asfatty acids with longer carbon chains (up to C50), or mixtures thereof.As for fatty alcohols, the amount of fatty acids required to support thefoam system is inversely related to the length of its carbon chain.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have at least one double bond. A further class of foam adjuvantagent includes a branched fatty alcohol or fatty acid. The carbon chainof the fatty acid or fatty alcohol also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid.

An important property of the fatty alcohols and fatty acids used incontext of the composition of the present invention is related to theirtherapeutic properties per se. Long chain saturated and mono unsaturatedfatty alcohols, e.g., stearyl alcohol, erucyl alcohol, arachidyl alcoholand behenyl alcohol (docosanol) have been reported to possess antiviral,antiinfective, antiproliferative and antiinflammatory properties (see,for example, U.S. Pat. No. 4,874,794). Longer chain fatty alcohols,e.g., tetracosanol, hexacosanol, heptacosanol, octacosanol,triacontanol, etc., are also known for their metabolism modifyingproperties and tissue energizing properties. Long chain fatty acids havealso been reported to possess anti-infective characteristics.

Thus, in preferred embodiments of the present invention, a combined andenhanced therapeutic effect is attained by including both a nonsteroidalimmunomodulating agent and a therapeutically effective foam adjuvant inthe same composition, thus providing a simultaneous anti-inflammatoryand antiinfective effect from both components. Furthermore, in a furtherpreferred embodiment, the composition concurrently comprises anonsteroidal immunomodulating agent, a therapeutically effective foamadjuvant and a therapeutically active oil, as detailed above. Suchcombination provides an even more enhanced therapeutic benefit. Thus,the foamable carrier, containing the foam adjuvant provides an extratherapeutic benefit in comparison with currently used vehicles, whichare inert and non-active.

The foam adjuvant according to preferred embodiments of the presentinvention includes a mixture of fatty alcohols, fatty acids and hydroxyfatty acids and derivatives thereof in any proportion, providing thatthe total amount is 0.1% to 5% (w/w) of the carrier mass. Morepreferably, the total amount is 0.4%-2.5% (w/w) of the carrier mass.

The foam of the present invention may further optionally include avariety of formulation excipients, which are added in order to fine-tunethe consistency of the formulation, protect the formulation componentsfrom degradation and oxidation and modify their consistency. Suchexcipients may be selected, for example, from stabilizing agents,antioxidants, humectants, preservatives, colorant and odorant agents andother formulation components, used in the art of formulation.

Propellants

Aerosol propellants are used to generate and administer the foamablecomposition as a foam. Suitable propellants include volatilehydrocarbons such as butane, propane, isobutane and fluorocarbon gases,or mixtures thereof.

In an embodiment of the present invention the propellant is AP 70 whichis a mixture of propane, isobutene and butane. In another embodiment thepropellant is AP 46 which is a similar mixture of propane, isobutene andbutane but having a lower pressure. AP 70 offers about 50% higherpressure than AP 46.

The propellant makes up about 3-25 wt % of the foamable composition. Insome circumstances the propellant may be up to 35%. The propellants areused to generate and administer the foamable composition as a foam. Thetotal composition including propellant, foamable compositions andoptional ingredients can be referred to as the foamable composition.

Alcohol and organic solvents render foams inflammable. It has beensurprisingly discovered that fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMOs), which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition. A test according to European Standard prEN 14851, titled“Aerosol containers—Aerosol foam flammability test” revealed thatcompositions containing an organic carrier that contains a hydrophobicorganic carrier and/or a polar solvent, which are detected asinflammable when a hydrocarbon propellant is used, become non-flammable,while the propellant is an HFC propellant.

Such propellants include, but are not limited to, hydrofluorocarbon(HFC) propellants, which contain no chlorine atoms, and as such, fallcompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect include propellantsmade by DuPont under the registered trademark Dymel, such as 1,1,1,2tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane(Dymel 227). HFCs possess Ozone Depletion Potential of 0.00 and thus,they are allowed for use as propellant in aerosol products.

Notably, the stability of foamable emulsions including HFC as thepropellant can be improved in comparison with the same composition madewith a hydrocarbon propellant.

In one or more embodiments foamable compositions comprise a combinationof a HFC and a hydrocarbon propellant such as n-butane or mixtures ofhydrocarbom propellants such as propane, isobutane and butane.

Aging

In order to project the potential shelf life and stability of thecompositions and their ingredients particularly active or benefit agentsthe compositions can subjected to a number of tests, includingcentrifugation to look for resistance to creaming, phase separation; oneor more freeze thaw cycles, standing at room and higher temperatures asan indicator of resistance to aging.

Cosmetically or Pharmaceutically Active Agents

In one or more embodiments, the foamable composition of the presentinvention is a carrier of a cosmetically or pharmaceutically activeagent(s). The agents may be introduced into an aqueous phase (i.e.,water), or a hydrophobic phase (e.g., hydrophobic solvent or oilglobules). Exemplary, non binding and cosmetically or pharmaceuticallyactive agents include, but are not limited to an anti-infective, anantibiotic, an antibacterial agent, an antifungal agent, an antiviralagent, an antiparasitic agent, an steroidal antiinflammatory agent, animmunosuppressive agent, an immunomodulator, an immunoregulating agent,a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, avitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, avitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, avitamin F derivative, vitamin K, a vitamin K derivative, a wound healingagent, a disinfectant, an anesthetic, an antiallergic agent, an alphahydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, aprotein, a peptide, a neuropeptide, a allergen, an immunogenicsubstance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylicacid, azelaic acid, sebacic acid, adipic acid, fumaric acid, a retinoid,an antiproliferative agent, an anticancer agent, a photodynamic therapyagent, an anti-wrinkle agent, a radical scavenger, a metal oxide (e.g.,titanium dioxide, zinc oxide, zirconium oxide, iron oxide), siliconeoxide, an anti wrinkle agent, a skin whitening agent, a skin protectiveagent, a masking agent, an anti-wart agent, a refatting agent, alubricating agent and mixtures thereof. Yet, in certain embodiments, oneor more components of the oil bodies or sub-micron globules act possessa therapeutic property, such as detailed hereinabove, and thus, in suchembodiments, the oil bodies or sub-micron globules can be consideredherein as active agents.

Composition and Foam Physical Characteristics

A pharmaceutical or cosmetic composition manufactured using the foamcarrier according to one or more embodiments of the present invention isvery easy to use. When applied onto the afflicted body surface ofmammals, i.e., humans or animals, it is in a foam state, allowing freeapplication without spillage. Upon further application of a mechanicalforce, e.g., by rubbing the composition onto the body surface, it freelyspreads on the surface and is rapidly absorbed.

The foam composition of the present invention creates a stableformulation having an acceptable shelf-life of at least one year, or atleast two years at ambient temperature. A feature of a product forcosmetic or medical use is long term stability. Propellants, which are amixture of low molecular weight hydrocarbons, tend to impair thestability of emulsions. It has been observed, however, that foamcompositions according to the present invention are surprisingly stable.Following accelerated stability studies, they demonstrate desirabletexture; they form fine bubble structures that do not break immediatelyupon contact with a surface, spread easily on the treated area andabsorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam.

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery;

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery;

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity;

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery;

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance;and

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administratable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

A further aspect of the foam is breakability. The foam of the presentinvention is thermally stable, yet breaks under sheer force. Sheer-forcebreakability of the foam is clearly advantageous over thermally-inducedbreakability. Thermally sensitive foams immediately collapse uponexposure to skin temperature and, therefore, cannot be applied on thehand and afterwards delivered to the afflicted area.

Another property of the foam is density (specific gravity), as measuredupon release from the aerosol can. Typically, foams have specificgravity of (1) less than 0.12 g/mL; or (2) the range between 0.02 and0.12; or (3) the range between 0.04 and 0.10; or (4) the range between0.06 and 0.10.

Fields of Pharmaceutical Applications

By including oil bodies or sub-micron globules and optionally,additional active agents in the compositions of the present invention,the composition are useful in treating an animal or a human patienthaving any one of a variety of dermatological disorders that include dryand/or scaly skin as one or their etiological factors (also termed“dermatoses”), such as classified in a non-limiting exemplary manneraccording to the following groups:

Dermatitis including contact dermatitis, atopic dermatitis, seborrheicdermatitis, nummular dermatitis, chronic dermatitis of the hands andfeet, generalized exfoliative dermatitis, stasis dermatitis; lichensimplex chronicus; diaper rash;

Bacterial infections including cellulitis, acute lymphangitis,lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneousinfections, staphylococcal scalded skin syndrome, folliculitis,furuncles, hidradenitis suppurativa, carbuncles, paronychial infections,erythrasma;

Fungal Infections including dermatophyte infections, yeast Infections;parasitic Infections including scabies, pediculosis, creeping eruption;

Viral Infections;

Disorders of hair follicles and sebaceous glands including acne,rosacea, perioral dermatitis, hypertrichosis (hirsutism), alopecia,including male pattern baldness, alopecia areata, alopecia universalisand alopecia totalis; pseudofolliculitis barbae, keratinous cyst;

Scaling papular diseases including psoriasis, pityriasis rosea, lichenplanus, pityriasis rubra pilaris;

Benign tumors including moles, dysplastic nevi, skin tags, lipomas,angiomas, pyogenic granuloma, seborrheic keratoses, dermatofibroma,keratoacanthoma, keloid;

Malignant tumors including basal cell carcinoma, squamous cellcarcinoma, malignant melanoma, paget's disease of the nipples, kaposi'ssarcoma;

Reactions to sunlight including sunburn, chronic effects of sunlight,photosensitivity;

Bullous diseases including pemphigus, bullous pemphigoid, dermatitisherpetiformis, linear immunoglobulin A disease;

Pigmentation disorders including hypopigmentation such as vitiligo,albinism and postinflammatory hypopigmentation and hyperpigmentationsuch as melasma (chloasma), drug-induced hyperpigmentation,postinflammatory hyperpigmentation;

Disorders of cornification including ichthyosis, keratosis pilaris,calluses and corns, actinic keratosis;

Pressure sores;

Disorders of sweating; and

Inflammatory reactions including drug eruptions, toxic epidermalnecrolysis; erythema multiforme, erythema nodosum, granuloma annulare.

According to one or more embodiments of the present invention, thecompositions are also useful in the therapy of non-dermatologicaldisorders by providing transdermal delivery of an active nonsteroidalimmunomodulating agent that is effective against non-dermatologicaldisorders.

The same advantage is expected when the composition is topically appliedto a body cavity or mucosal surface (e.g., the mucosa of the nose,mouth, eye, ear, vagina or rectum) to treat conditions such as chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum.

Other foamable compositions are described in: U.S. Publication No.05-0232869, published on Oct. 20, 2005, entitled NONSTEROIDALIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 05-0205086, published on Sep. 22, 2005, entitled RETINOIDIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0018937, published on Jan. 26, 2006, entitled STEROID KIT ANDFOAMABLE COMPOSITION AND USES THEREOF; U.S. Publication No. 05-0271596,published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION ANDUSES THEREOF; U.S. Publication No. 06-0269485, published on Nov. 30,2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S.Publication No. 07-0020304, published on Jan. 25, 2007, entitledNON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0193789, published on Aug. 31, 2006, entitled FILM FORMINGFOAMABLE COMPOSITION; U.S. patent application Ser. No. 11/732547, filedon Apr. 4, 2007, entitled ANTI-INFECTION AUGMENTATION OF FOAMABLECOMPOSITIONS AND KIT AND USES THEREOF; U.S. Provisional PatentApplication No. 60/789186, filed on Apr. 4, 2006, KERATOLYTIC ANTIFUNGALFOAM; U.S. Provisional Patent Application No. 0/815948, filed on Jun.23, 2006, entitled FOAMABLE COMPOSITIONS COMPRISING A CALCIUM CHANNELBLOCKER, A CHOLINERGIC AGENT AND A NITRIC OXIDE DONOR; U.S. ProvisionalPatent Application No. 60/818634, filed on Jul. 5, 2006, entitledDICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICAL COMPOSITIONSTHEREOF; U.S. Provisional Patent Application No. 60/843140, filed onSep. 8, 2006, entitled FOAMABLE VEHICLE AND VITAMIN PHARMACEUTICALCOMPOSITIONS THEREOF, all of which are incorporated herein by referencein their entirety with reference to any of the active ingredients;penetration enhancers; humectants; moisturizers; listed therein can beapplied herein and are incorporated by reference.

The following examples further exemplify the benefit agent foamablepharmaceutical carriers, pharmaceutical compositions thereof, methodsfor preparing the same, and therapeutic uses of the compositions. Theexamples are for the purposes of illustration only and are not intendedto be limiting. Many variations may be carried out by one of ordinaryskill in the art and are contemplated within the full scope of thepresent invention.

Methodology

A general procedure for preparing foamable compositions is set out in WO2004/037225, which is incorporated herein by reference.

General PFF Preparation Nano Foams

Nano Emulsion Foam Stabilized with Hydrocolloids polymers

-   -   1. Mix oily phase ingredients and heat to 75° C. to melt all        ingredients and obtain homogeneous mixture.    -   2. Mix polymers in water with heating or cooling as appropriate        for specific polymer.    -   3. Add all other water soluble ingredients to water-polymer        solution and heat to 75° C.    -   4. Add slowly external phase to internal phase at 75° C. under        vigorous mixing and homogenize to obtain fine emulsion.    -   5. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   6. The fine emulsion oily droplets are further finely dispersed        using high pressure homogenizer (Model M-110Y Microfluidezer®        processor, Microfluidics Corp, USA) at 1000-1500 bars pressure,        4 to 8 cycles. The temperature is kept above 40° C. during        homogenization process until viscosity drops.        Nano Emulsion Foam Stabilized With Acrylates polymers    -   1. Mix oily phase ingredients and heat to 60° C. to melt all        ingredients and obtain homogeneous mixture.    -   2. Disperse the Acrylate polymer in the oily phase.    -   3. Mix all water soluble ingredients to water solution and heat        to 60° C.    -   4. Add slowly external phase to internal phase at 60° C. under        vigorous mixing and homogenize to obtain fine emulsion.    -   5. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   6. The fine emulsion oily droplets are further finely dispersed        using high pressure homogenizer (Model M-110Y Microfluidezer®        processor, Microfluidics Corp, USA) at 1000-1500 bars pressure,        4 to 8 cycles. The temperature is kept above 40° C. during        homogenization process until viscosity drops.

Emulsion Foam

-   -   1. Mix oily phase ingredients and heat to 75° C. to melt all        ingredients and obtain homogeneous mixture.    -   2. Mix polymers in water with heating or cooling as appropriate        for specific polymer. Whilst the polymers may be added instead        into the oily phase it was found to be advantageous to prepare        them in the water phase.    -   3. Add all other water soluble ingredients to water-polymer        solution and heat to 75° C.    -   4. Add slowly internal phase to external phase at 75° C. under        vigorous mixing and homogenize to obtain fine emulsion.        Alternatively the external phase is added slowly to the internal        phase.    -   5. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   6. Cool to room temperature.

Waterless Foam

-   -   1. Dissolve the polymers in the main solvent with heating or        cooling as appropriate for specific polymer. Add the all other        ingredients and heat to 75° C. to melt and dissolve the various        ingredients.    -   2. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   3. Cool to room temperature.

Oily Waterless Foam

-   -   1. Mix all ingredients excluding polymers and heat to 75° C. to        melt and dissolve and obtain homogeneous mixture.    -   2. Mix well and cool to below 40° C. and add the polymers and        sensitive ingredients with moderate mixing.    -   3. Cool to room temperature.        Oily Foam With phospholipids and/or Water    -   1. Swell the phospholipids in the main oily solvent under mixing        for at least 20 minutes until uniform suspension is obtained.    -   2. Add all other ingredients excluding polymers and heat to        75° C. to melt and dissolve and obtain homogeneous mixture.    -   3. Mix well and cool to below 40° C. and add the polymers and        sensitive ingredients with moderate mixing.    -   4. Cool to room temperature.    -   5. In case of polymers dissolved in water or organic solvent,        dissolve the polymers in the solvent with heating or cooling as        appropriate for specific polymer and add to the oily mixture        under vigorous mixing at ˜40° C.

Canisters Filling and Crimping

Each aerosol canister is filled with PFF and crimped with valve usingvacuum crimping machine.

Pressurizing

Propellant Filling

Pressurizing is carried out using a hydrocarbon gas or gas mixture

Canisters are filled and then warmed for 30 sec in a warm bath at 50° C.and well shaken immediately thereafter.

Closure Integrity Test.

Each pressurized canister is subjected to bubble and crimping integritytesting by immersing the canister in a 60° C. water bath for 2 minutes.

Canisters are observed for leakage as determined by the generation ofbubbles. Canisters releasing bubbles are rejected.

Tests

By way of non limiting example the objectives of hardness, collapsetime, viscosity, bubble size, nano size and FTC stability tests arebriefly set out below as would be appreciated by a person of the art.

Hardness

-   -   LFRA100 instrument is used to characterize hardness. A probe is        inserted into the test material. The resistance of the material        to compression is measured by a calibrated load cell and        reported in units of grams on the texture analyzer instrument        display. Preferably at least three repeat tests are made. The        textural characteristics of a dispensed foam can effect the        degree of dermal penetration, efficacy, spreadability and        acceptability to the user. The results can also be looked at as        an indicator of softness. Note: the foam sample is dispensed        into an aluminum sample holder and filled to the top of the        holder.

Collapse Time

-   -   Collapse time (CT) is examined by dispensing a given quantity of        foam and photographing sequentially its appearance with time        during incubation at 36° C. It is useful for evaluating foam        products, which maintain structural stability at skin        temperature for at least 1 min.

Viscosity

-   -   Viscosity is measured with Brookfield LVDV-II +PRO with spindle        SC4-25 at ambient temperature and 10, 5 and 1 RPM. Viscosity is        usually measured at 10RPM. However, at about the apparent upper        limit for the spindle of ˜>50,000CP, the viscosity at 1RPM may        be measured, although the figures are of a higher magnitude.        Unless otherwise stated viscosity of the pre foam formulation is        provided.

FTC (Freeze Thaw Cycles)

-   -   To check the foam appearance under extreme conditions of        repeated cycles of cooling, heating, (first cycle) cooling,        heating (second cycle) etc., commencing with −10° C. (24 hours)        followed by +40° C. (24 hours) measuring the appearance and        again repeating the cycle for up to four times.

Creaming by Centrifugation:

-   -   1. Principle of test        -   The centrifugation used in this procedure serves as a stress            condition simulating the aging of the liquid dispersion            under investigation. Under these conditions, the centrifugal            force applied facilitates the coalescence of dispersed            globules or sedimentation of dispersed solids, resulting in            loss of the desired properties of the formulated dispersion.    -   2. Procedure        -   2.1. Following preparation of the experimental            formulation/s, allow to stand at room temperature for ≧24 h.        -   2.2. Handle pentane in the chemical hood. Add to each            experimental formulation in a 20-mL glass vial a quantity of            pentane equivalent to the specified quantity of propellant            for that formulation, mix and allow formulation to stand for            at least 1 h and not more than 24 h.        -   2.3. Transfer each mixture to 1.5 mL microtubes. Tap each            microtube on the table surface to remove entrapped air            bubbles.        -   2.4. Place visually balanced microtubes in the centrifuge            rotor and operate the centrifuge at one or more of 10,000            rpm for 10 min, 3,000 rpm for 10 min or at 1,000 rpm for 10            min.

Bubble Size:

-   -   Foams are made of gas bubbles entrapped in liquid. The bubble        size and distribution reflects in the visual texture and        smoothness of the foam. Foam bubbles size is determined by        dispensing a foam sample on a glass slide, taking a picture of        the foam surface with a digital camera equipped with a macro        lens. The diameter of about 30 bubbles is measured manually        relatively to calibration standard template. Statistical        parameters such as mean bubble diameter, standard deviation and        quartiles are then determined. Measuring diameter may also be        undertaken with image analysis software. The camera used was a        Nikon D40X Camera (resolution 10 MP) equipped with Sigma Macro        Lens (ref: APO MACRO 150 mm F2.8 EX DG HSM). Pictures obtained        are cropped to keep a squared region of 400 pixels×400 pixels.

Nano Size:

-   -   The light microscope enables observing and measuring particles        from few millimeters down to one micron. Light microscope is        limited by the visible light wavelength and therefore is useful        to measuring size of particles above 800 nanometers and        practically from 1 micron (1,000 nanometers).Measuring smaller        particle, nano size range, is performed by a Dynamic light        scattering (DLS), sometimes referred to as Photon Correlation        Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS). The        method is a non-invasive, well-established technique for        measuring the size of molecules and particles typically in the        sub micron region, and with the latest technology lower than 1        nanometer. Measurements are usually made without a vacuum, but        wherever appropriate a vacuum can be applied. A Malvern nano        sizeris SB-A-018 nano zs Serial num: MAL 50041 for example may        be used.

EXAMPLES

The following examples exemplify the compositions and methods describedherein. The examples are for the purposes of illustration only and arenot intended to be limiting. Many variations will suggest themselves andare within the full intended scope of the appended claims.

Example 1 SME-Based Foamable Composition 1. Emulsion Formula

% w/w A Mineral oil (oil) 5.60 Isopropyl myristate (emollient) 5.60Glyceryl monostearate (emollient) 0.45 PEG-40 Stearate (surfactant) 2.60Stearyl alcohol (foam adjuvant) 0.85 B Xanthan gum (gelling agent) 0.26Methocel K100M (gelling agent) 0.26 Polysorbate 80 (surfactant) 0.90Water 74.88 C Preservative 0.60 D Propellant 8.00 100.00

2. Emulsion Preparation

Oil Phase (A): The ingredients of the Oil Phase were preheated to thesame temperature, e.g., 40-75° C., and then were combined with mixing.Oil soluble cosmetic or pharmaceutical active ingredients and optionaloil soluble formulation ingredients are added with agitation to the OilPhase mixture.

Aqueous Phase (B): Water gelling agent and surfactant were dissolved inwater, with agitation. The solution was warmed to 50-70° C. Watersoluble cosmetic or pharmaceutical active ingredients and optional watersoluble ingredients were added with agitation to the Aqueous Phasemixture.

The warm Oil Phase was gradually poured into the warm Aqueous Phase,with agitation, followed by Ultraturax homogenization. The mixture wasallowed to cool down to ambient temperature. In case of heat sensitiveactive ingredients, the active ingredient can be added with agitation tothe mixture after cooling to ambient temperature. The mixture, atambient temperature, was added to an aerosol container, the containerwas sealed and appropriate amount of propellant (5-25 w % of thecomposition mass) was added under pressure into the container.

Microscopic observation of the resulting emulsion revealed mean particlesize of 2 to 4 microns.

3. Conversion of the Emulsion to Nanoemulsion (Pre-Foam Composition)

The emulsion was passed through a microfluidizer, Microfluidics M-110YMicrofluidizer® M-110Y about 10 cycles, using ice to avoid heating theformula.

4. Packaging and Pressurizing of the Nanoemulsion Composition

A nanoemulsion composition (46 gram) was introduced into a 60 mlmonoblock aluminum can. The can was sealed with an aerosol valve and 4gram of liquefied propellant (propane butane isobutene mixture) wasadded through the valve.

5. Characterization of the Nano Emulsion

Particle size distribution was determined using a Malvern nanosizer™instrument. The pre-foam composition showed two peaks of 188 and 59nanometers. Four days after packaging and pressurizing of thecomposition, foam was released from the aerosol can and light microscopeobservation revealed small population of ˜1 micron globules andsubstantial Brownian movement indicating that majority of oil dropletsare of sub-micron or nano-scale.

6. Packaging and Pressurizing of the Nano Emulsion Composition

An emulsion (46 gram) was added into a 60 ml monoblock aluminum can. Thecan was closed with an aerosol valve and 4 gram of liquefied propellant(propane/butane mix) was added through the valve. The propellant can beany compressed and liquefied gas, currently used as aerosol propellant.The final concentration of propellant can vary from 3% to 25%.

Example 2 Oil Bodies Based Foamable Compositions

NAT01 NAT02 NAT03 NAT04 % w/w % w/w % w/w % w/w Natural Oleosomes 30.0030.00 30.00 30.00 (Natrulon OSF)* Hydroxypropylmethycellulose 0.25 0.25— — (gelling agent) Xanthan Gum (gelling agent) 0.25 0.25 — — CocamideDEA (surfactant) 1.00 1.00 Polsorbate 20 (surfactant) — — — 1.00 Waterpure 68.50 69.50 69.00 69.00 100.00 100.00 100.00 100.00 Foam PropertiesFoam Quality E E E G Stability RT Stable Stable Creaming Creaming After72 After 72 Hr. Hr. *Natrulon OSF is the trade name of Lonza Inc.

The production of the compositions NATO1 included the following steps:

-   -   1. Add the polymeric agents (Hydroxypropylmethycellulose and        Xanthan Gum) to the Natrulon OSF at 50° C. and mix during 10        minutes while the preparation cools down to Room Temperature.    -   2. Add the Cocamide DEA with mixing.    -   3. Fill the composition aerosol canisters and add 8% of        propellant.

The production of the compositions NATO2 included the following steps:

-   -   1. Add the polymeric agents (Hydroxypropylmethycellulose and        Xanthan Gum) to the Natrulon OSF at 50° C. and mix during 10        minutes while the preparation cools down to Room Temperature.    -   2. Fill the composition aerosol canisters and add 8% of        propellant.

The production of the compositions of NATO3 included the followingsteps:

-   -   1. Add the cool water to the Natrulon OSF and mix during 10        minutes.    -   2. Add the Cocamide DEA with mixing.    -   3. Fill the composition aerosol canisters and add 8% of        propellant.

The production of the compositions of NAT04 included the followingsteps:

-   -   1. Add the cool water to the Natrulon OSF and mix during 10        minutes.    -   2. Add Polysorbate 20 with mixing.    -   3. Fill the composition aerosol canisters and add 8% of        propellant.

Example 3 Further Foamable Compositions Containing Oil Bodies

% w/w % w/w Caprylic/capric triglyceride 5.00 — (MCT oil) Stearylalcohol 0.90 — Natrulon OSF* 10.00 10.00 Methylcellulose 0.25 0.25Xanthan gum 0.25 0.25 PEG-40 stearate 2.50 2.50 Polysorbate 80 0.90 0.90Preservative 0.50 0.50 Purified water to 100% to 100% Propellant 8.00

Formation Properties

Emulsion visual test Uniform Uniform Viscosity (Spindle SC4-31)(cP)1,428 868.5 Centrifugation (prior to propellant addition) Stable Stable(10 min/3,000 rpm) PH (direct, prior to propellant addition) 6.04 6.72Foam Quality G E Density 0.0337 0.0339

Example 4 Exploring Some Limitations On Making Nano-Emulsions

Ingredients NEP002 NEP006 Isopropyl myristate 6.00 6.00 light Mineraloil 6.00 6.00 Glyceryl 0.50 1.00 monostearate PEG-40 stearate 3.00 6.00Stearyl alcohol 1.00 1.00 Xanthan gum 0.30 0.30 Methocel K100M 0.30 0.30Polysorbate 80 1.00 2.00 Water, purified 81.30 76.80 Sharomix 824 0.600.60 Total 100.00 100.00 Propellant 8.00 8.00 Cycles 4 3 Pressure (Bar)1000-1500 Comments inter alia Emulsion broke after Emulsion still as tonon suitability first cycle broke after first for nano emulsion cyclewith double preparation surfactant that of 002.

-   Comment: None of the above two formulations were found suitable for    preparation of a nano emulsion using a high pressure homogenizer.    This indicates that the selection of surfactants that can hold the    emulsion together whilst being subject to the effects of being    processed in a high speed homogenizer is of importance in the    preparation of nano emulsions. Formulations were also prepared with    a combination of high and medium levels of petrolatum and mineral    oil (42% and 18% respectively) and with medium levels of petrolatum    (25%). In both cases the formulation was found to be too viscous to    be used with the nano emulsion. None of the above formulations were    found suitable for preparation of a nano emulsion using a high    pressure homogenizer primarily because of their high viscosity.    Nevertheless, it is believed that the issue of viscosity may be    overcome-able by warming the formulation and or reducing the levels    of petrolatum. A formulation containing a powder suspension was also    found to be unsuitable due to sedimentation. Accordingly, to the    extent a formulation is to comprise a suspension that element may be    introduced after a stable nano emulsion carrier is produced rather    than during the process. For satisfactory processing the emulsion    should have sufficient stability to withstand gentle heating.

Example 5 Behavior of Stable Homogeneous Emulsions With Two DifferentOils

Ingredients NEP007 NEP008 Diisopropyl adipate (DISPA) 20.00 PPG 15Stearyl ether (PPG) 20.00 Steareth-2 3.67 4.00 Steareth 21 2.33 1.00Carboxy methyl cellulose 0.50 0.50 Water, purified 72.90 73.90 Sharomix824 0.60 0.60 Total 100.00 100.00 Propellant 8.00 8.00 Cycles 5 6Pressure (Bar) 1000-1500 1000-1500 Visual Inspection HomogeneousHomogeneous Shakability Yes Yes F.Q. Good Fairly Good Cetrif: 3000 RPMStable Stable Cetrif: 10000 RPM 30% 90% Creaming Creaming Density 0.057N/R Viscosity(cP) 10 RPM 4734.99 3775.19 Collapse Time (sec.) >300 >300PFF Size Study: Diameter (nm)/% volume-25 C. 718/92.4% 2590/86.8%147/7.6% * 243/13.2 * Dilution 1:80 w/w with 1:80 w/w with vacuum vacuumFOAM Size Study: Diameter (nm)/% volume-25 C. 2790/82.4% 328/17.6%Dilution 1:80 w/w with 1:80 w/w with vacuum * vacuum * *-example of*-example of results results achieved achieved FTC (4 cycles) QualityGood Density 0.046 Collapse time (sec.) >300 >300 1 Month 40 C. QualityExcellent Fairly Good Density 0.045 Collapse time (sec.) >300 Diameter(nm)/% volume-25 C. 3410/100% Dilution 1:80 w/w with vacuum *

-   Comment: After 5 or 6 cycles of high pressure homogenization the    emulsion appears to behave differently depending on which oil is    used. In the presence of 20% DISPA a good quality foam is produced    containing large nano particles primarily in the region of 700    nanometers and which can withstand four freeze thaw cycles (FTC) but    which reverts to form globules of over 3 microns after a month. In    contrast in the presence of 20% PPG foam quality is fairly good and    the oil droplets have a diameter primarily in the region of 2600    nanometers or 2.6 microns.

Example 6 Production of Stable Homogeneous Emulsions With Petrolatum

Ingredients NEP010 White Petrolatum (sofmetic) 7.14 Steareth-2 1.43Steareth 21 4.29 Carboxy methyl cellulose 0.36 Water, purified 86.18TEA, q.s. to pH: to pH 4.77 Sharomix 824 0.60 Total 100.00 Propellant8.00 Cycles 6 Pressure (Bar) 1000-1500 Visual Inspection HomogeneousShakability Yes F.Q. Excellent* Cetrif: 3000 RPM Stable Cetrif: 10000RPM 98% translucent Viscosity(cP) 10 RPM 7.00 Collapse Time (sec.) >300PFF Size Study: Diameter (nm)/% volume- 125/100% 25 C. Dilution 1:10 v/vFOAM Size Study: Diameter (nm)/% volume-  275/22.1% 25 C. 96.8/16.1%26.2/55.4% Dilution 1:10 w/w * After 2 weeks FG FTC (4 cycles) QualityGood Density 0.036 Collapse Time (sec.) >300

-   Comment: Petrolatum produces formulations with higher viscosity as    it is a viscous material. Nevertheless, by reducing the content of    petrolatum and by gentle warming it is possible to make nano    emulsions with petrolatum. Not only was the above formula homogenous    and stable to centrifugation but it produced foam of excellent    quality having pre foam nano particles size primarily in the region    of 125 nanometers and the majority of the foam nano particles being    in the region of 26 nanometers. Remarkably, the formulation    viscosity showed a dramatic reduction. Without being bound by any    theory this may be connected to the high pressure mechanical    manipulation of petrolatum and possible breakdown of polymer and    further it seems that there can be a close connection between    reduction of viscosity and successful smaller nano emulsion    formulations. On the other hand by using a different polymer    carbomer an acrylic polymer it was possible to achieve a successful    larger nano emulsion with high viscosity that remained stable for a    month at 40C; stable to centrifugation and stable to FTC as can be    seen in Formula 12 Example 8

Example 7 Examination of Number of Cycles

NEP011-4C NEP011-6C Isopropyl myristate 5.00 5.00 Octyl dodecanol 5.005.00 Cetearyl alcohol 3.00 3.00 Polyoxyl 100 monostearate 2.50 2.50Methocel K100 LV 0.20 0.20 Carbomer 934P 0.40 0.40 Polysorbate 80 0.500.50 Propylene glycol 3.34 3.34 Water, purified 79.81 79.81 TEA, q.s. topH: to pH 4.60 to pH 4.70 Propyl Paraben 0.10 0.10 Methyl paraben 0.150.15 Total 100.00 100.00 Propellant 8.00 8.00 Cycles 4 6 Pressure (Bar)1000-1500 1000-1500 Visual Inspection Homogenous Homogenous ShakabilityYes Yes F.Q. Excellent Excellent Cetrif: 3000 RPM Stable Stable Cetrif:10000 RPM Stable Stable Density 0.041 Viscosity(cP) 10 RPM 5198.89 52.99Collapse Time (sec.) >300 PFF Size Study: * Diameter (nm)/% volume-25 oC570/100% 251/100% Dilution 1:80 w/w 1:80 w/w FOAM Size Study: Diameter(nm)/% volume-25 C.  667/85.2% 99.1/4%  5220/10.4% 297/100% Dilution1:80 w/w 1:80 w/w FTC (4 cycles) Quality Excellent Density 0.038*Separation after 5 days, reversible

-   Comment: The question of how many cycles are preferable was    examined. Using too few cycles may not produce emulsions with oil    droplets in the lower nanometer range. On the other hand there is    some concern that using too many cycles may destroy the ability to    make good quality stable homogenous nano foam. Nano emulsions are    fragile and metastable. Much energy work is required to reduce oil    droplets size. The energy is invested in creating large interfacial    area between the two immiscible phases. At first the energy input    contributes to creation of the interfacial area and particle size    reduction. At some point, an extra energy does not contribute any    more to size reduction and instead causes particle collapse,    increases in particle size and reduction in interfacial area. Every    process of emulsification and energy input has an optimum which will    be related for example to formulation, mean of energy input,    homogenization and other criteria. It was noted that in general    three cycles was insufficient and that signs of nano emulsion    qualities of translucent foam with a blue tint became more    recognizable from four cycles. Thus a study was made to compare four    with six cycles. It can be seen that after four cycles the pre foam    formulation had a nano size primarily in the region of 570    nanometers and a reasonable viscosity in the range of 5000 Cp.    However, when the processing was extended to six cycles there was a    remarkable reduction in viscosity of about a hundred fold to the    range of 50 cP and that the nano size of the pre foam formulation    was halved. Interestingly, when foam was produced the nano size was    substantially the same, suggesting that conversion to foam does not    disturb the nano particle size to any significant extent. On the    other hand as can be seen below there a dramatic effect on bubble    size is observed between a pre and post nano processed formulation.    Also of note is the observation that dramatic reduction in viscosity    is seen with the polymeric combination of methocel and carbomer.    However, as seen in Example 8 below, when the polymeric agent is    only pH adjusted carbomer the formulation remains with high    viscosity after 6 cycles

Example 8 Behavior of Stable Homogeneous Emulsions With a ThirdDifferent Oil

Ingredients NEP012 Isopropyl myristate 20.00 Steareth-2 4.34 Steareth 212.66 Carbomer 934P 0.50 Propylene glycol 3.00 Water, purified 69.00 TEA,q.s. to pH: to pH 4.66 Sharomix 824 0.50 Total 100.00 Propellant 8.00Cycles 6 Pressure (Bar) 1000-1500 Visual Inspection HomogenousShakability Yes F.Q. Excellent Centrifugation: 3000 RPM StableCentrifugation: 10000 RPM Stable Density 0.065 Viscosity(cP) 10 RPM21595.39 Collapse Time (sec.) >300 PFF Size Study: Diameter (nm)/%volume-25 oC   802/100% Dilution 1:80 w/w FOAM Size Study: Diameter(nm)/% volume-25 oC  688/90.8% 5240/7.3% 110/1.8% Dilution 1:80 w/w FTCQuality Excellent Density 0.073 Collapse Time (sec.) >300 1 month 40 C.Quality Excellent Density 0.048 Collapse Time (sec.) >300 Diameter(nm)/% volume-25 C. 831//71.4% 154/3.3% 5040/25.3% Dilution 1:80 w/w

-   Comment: Like the formulations discussed in Example 5, this example    is based on 20% oil. The oil is isopropyl myristate, which is a    third type of oil. Here the formula was pH adjusted with    triethanolamine (TEA). The oil droplet size for the pre-foam    formulation was of the order of 800 nanometers and that of the foam    was of the order of 700 namometers indicating that isopropyl    myristate is not dissimilar from DISPA in relation to the size of    resultant nano particles. Moreover, after a month at 40 C most of    the globules were of the order 830 nanometers. Of the three    formulations isopropyl myristate, made the best quality foam, which    likewise may more suit nano emulsion preparation albeit at the    higher end of the scale. The viscosity of the pre foam formulation    is high primarily due to the level of carbomer and the pH. At this    viscosity the composition is flowable but not really shakable.    However, upon addition of propellant the formulation is shakable.

Example 9 Examination of Effects of Reducing/Increasing SurfactantLevels

NEP013 NEP015 NEP014 Isopropyl myristate 10.00 10.00 10.00 light Mineraloil 10.00 10.00 10.00 Glyceryl monostearate 0.50 0.50 0.50 PEG-40stearate 3.20 2.40 1.60 Stearyl alcohol 1.50 1.50 1.50 Carbomer 934P0.40 0.40 0.40 Polysorbate 80 4.80 3.60 2.4 Propylene glycol 3.00 3.003.00 Water, purified 66.00 68.00 70.10 TEA, q.s. to pH: to pH 4.66 to pH4.71 to pH 4.60 Sharomix 824 0.60 0.60 0.50 Total 100.00 100.00 100.00Propellant 8.00 8.00 8.00 Cycles 6 6 6 Presion (Bar) 1000-1500 1000-15001000-1500 Visual Inspection Homogenous Homogenous Homo- (highly genoustranslucent) Shakability Yes Yes Yes F.Q. Excellent Excellent ExcellentCentrifugation: 3000 RPM Stable Stable Stable Centrifugation: 10000 RPMStable Stable Stable Density 0.052 0.045 0.042 Viscosity(cP) 10 RPM241.95 207.96 107.96 Collapse Time (sec.) >300 >300 >300 PFF Size Study:Diameter (nm)/% volume- 80.2/100% 105/100% 149/100% 25 C. Dilution 1:15v/v 1:20 v/v 1:20 v/v FOAM Size Study: Diameter (nm)/% volume-  104nm/88.7%,  120/88.2% 179/84.8 25 C. 4660 nm/11.3% 4740/11.8% 5280/15.2%Dilution 1:15 w/w 1:20 w/w 1:20 w/w with vacuum FTC Quality Good Density0.050 Collapse Time (sec.) >300 Diameter (nm)/% volume-  117/62.1% 25 C. 822/8%  3400/29.9% 1-Month 40 C. Quality Good Density 0.045 CollapseTime (sec.) >300 Diameter (nm)/% volume-  72.8/76.3% 25 C. 3290/23.7%Dilution 1:15 w/w

-   Comment: The surfactant concentrations of PEG-40 stearate and    Polysorbate 80 were decreased from 8% to 6% to 4% to examine the    effect of surfactant levels on nano sizing of the formulations and    foam. Whilst all the formulations produced foam of excellent quality    there was a clear and consistant effect on oil droplet size. As the    level of surfactant was reduced there was a corresponding increase    in nano size. Thus higher levels of surfactant support a lower nano    size. Approximately parallel reductions were also observed in    viscosity and in density as the surfactant levels were reduced. It    is also noteworthy that after a month at 40 C the globules size    remained substantially the same

Example 10 A Comparison of Bubble Size of Resultant Foam Before andAfter Processing the Formulation to Produce a Nano Composition

Notes to FIGS. 1A through 5C:

-   -   C0 means the formulation was not subject to nano processing.    -   C6 means the formulation was subject to 6 cycles of nano        processing.    -   AP 70 and AP 46 are propellants comprising similar mixtures of        propane, butane and isobutane but the former offers about 50%        more pressure.

In all cases observed as shown in FIGS. 1A through 5C, nano emulsionssurprisingly produced foam with a substantially larger foam bubble sizeranging from an increase of about a third to an increase of almost fourfold in magnitude, when the identical same formulation was subject tonano processing. Thus, by creating a nano emulsion it is possible togenerate foam of quality with a larger bubble size, which may internpositively influence the cosmetic elegance of the foam in that theformulation may have a more foam like feel with less of the sensationand greasy feeling that might be experienced with a cream or mousseAlso, the increased bubble size may contribute to ease of spreadability.It was also discovered that it is possible to manipulate bubble size bypropellant selection. So for example, bubble size was seen to increaseby about a third when a higher pressure hydrocarbon propellant wassubstituted in the same formulation

Example 11 A Comparison of Physical Properties of Resultant Foam Beforeand After Processing (Six Cycles) the Formulation to Produce a NanoComposition

-   Comment: In the above three cases formation of nano emulsions having    nano size particles resulted in a substantial reduction in the    formulation viscosity even though chemically the formulation    constituents were unchanged. No significant change of collapse time    was observed. Formulations which were non shakable prior to    processing were became shakable following processing. Also    remarkably formulations that produced only fairly good foam prior to    processing were improved such that, for example, excellent foam may    be formed. True nano emulsions appeared translucent with a blue hint    whereas prior to processing the emulsions were generally opaque.

1. A foamable oil in water nano emulsion composition comprising: (a) anano oil globule system, comprising substantially of sub-micron oilglobules; (b) about 0.1% to about 5% by weight of at least onestabilizing agent, selected from the group consisting of i. a non-ionicsurfactant, ii. an ionic surfactant, and iii. a polymeric agent; (c)water; and (d) a liquefied or compressed gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition wherein the oil, stabilizer and water are selected toprovide a composition that is substantially homogenous and resistant toaging; wherein the composition is contained in a pressurized containeris substantially flowable and provides a breakable foam upon release,which is thermally stable, yet breaks under sheer force; and wherein thebubble size of the resultant foam is significantly greater than thebubble size of the resultant foam from a composition with the sameingredients which has not been subject to nano processing. 2-20.(canceled) 1-20. (canceled)
 21. A foamable nano-emulsion compositioncomprising a carrier and a propellant, the carrier comprising: a. one ormore of a hydrophobic solvent, a polar solvent, an emollient, and amixture thereof, at a concentration of about 2% to about 50% by weightof the carrier; b. a stabilizing agent selected from the groupconsisting of a surface-active agent, a polymeric agent and a mixturethereof, wherein the surface-active agent comprises a polyoxyethylenealkyl ether, and wherein the polymeric agent comprises a water-solublecellulose ether; c. water; d. optionally a foam adjuvant; and whereinthe carrier comprises submicron oil globules; wherein the propellant isa liquefied or compressed gas propellant at a concentration of about 3%to about 25% by weight of the nano-emulsion composition; and wherein thecomposition is contained in a pressurized container and provides abreakable foam upon release.
 22. The composition of claim 21, whereinthe polar solvent is selected from the group consisting of a polyol,glycerol, propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol,a glycol, sulfoxide, dimethylsulfoxide (DMSO), dimethylformanide, methyldodecyl sulfoxide, dimethylacetamide, monooleate of ethoxylatedglycerides with 8 to 10 ethylene oxide units, azone(1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, isopropylmyristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate,capric/caprylic triglyceride, octylmyristate, dodecyl-myristate;myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketone, anamide, acetamide oleate, triolein, an alkanoic acid, caprylic acid, alactam compound, azone, an alkanol, a dialkylamino acetate, apolyethylene glycol, PEG200, PEG300, PEG400, PEG600, and a mixture ofany two or more thereof.
 23. The composition of claim 21, wherein theemollient is selected from the group consisting of hexyleneglycol,propylene glycol, an isostearic acid derivative, isopropyl palmitate,isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate,maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, acetylated oil bodies alcohol, cetyl acetate, phenyltrimethicone, glyceryl oleate, tocopheryl linoleate, a wheat germglyceride, arachidyl propionate, myristyl lactate, decyl oleate,propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityltetrastearate, neopentylglycol dicaprylate/dicaprate, isononylisononanoate, isotridecyl isononanoate, myristyl myristate, triisocetylcitrate, octyl dodecanol, sucrose esters of fatty acids, octylhydroxystearate, and a mixture of any two or more thereof.
 24. Thecomposition of claim 21, wherein the hydrophobic solvent is selectedfrom the group consisting of liquid oil, a vegetable oil, a marine oil,an animal oil, saturated oil, unsaturated oil, polyunsaturated oil,olive oil, corn oil, soybean oil, canola oil, cottonseed oil, coconutoil, sesame oil, sunflower oil, borage seed oil, syzigium aromaticumoil, hempseed oil, herring oil, cod-liver oil, salmon oil, flaxseed oil,wheat germ oil, evening primrose oil, poly-unsaturated fatty acid,omega-3 fatty acid, omega-6 fatty acids, linoleic acid, linolenic acid,gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA), docosahexaenoicacid (DHA), an essential oil, a therapeutically active oil, a siliconeoil, a non-volatile silicone, polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers, cyclic or linearpolydimethylsiloxanes containing from about 3 to about 9 silicon atoms,a volatile silicone, cyclomethicone and a mixture of any two or morethereof.
 25. The composition of claim 21, wherein the surface-activeagent u her comprises a non-ionic surface-active agent.
 26. Thecomposition of claim 21, wherein the surface-active agent furthercomprises a surfactant selected from the group consisting of apolysorbate, a polyoxyethylene fatty acid ester, a polyoxyethylene alkylether, a steareth, a sucrose ester, a partial ester of sorbitol and itsanhydrides, sorbitan monolaurate, a monoglyceride, a diglyceride,isoceteth-20, mono-, di-, and tri-esters of sucrose with fatty acids,steareth 2, steareth 21, ceteth-20, sorbitan monooleate, glycerylmonostearate, PEG 40 stearate, polyoxyl 100 monostearate, methyl glucosesesquistearate, polysorbate 80, a phospholipid, sodium lauryl sulphate,cocamidopropylbetaine, and a mixture of any two or more thereof.
 27. Thecomposition of claim 21, wherein the polymeric agent further comprises apolymeric agent selected from the group consisting of anaturally-occurring polymeric material, microcrystalline cellulose,hydrophobically-modified ethoxylated urethane, a carbomer,methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxypropyl methylcellulose, methylhydroxyethylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethylcellulose, xanthan gum, guar gum,carrageenin gum, locust bean gum, tragacanth gum, and a mixture of anytwo or more thereof.
 28. The composition of claim 21, wherein the foamadjuvant is selected from the group consisting of a fatty alcohol having15 or more carbons in its carbon chain; a fatty acid having 16 or morecarbons in its carbon chain; a fatty alcohol derived from beeswax; amixture of alcohols, a majority of which have at least 20 carbon atomsin a carbon chain; a fatty alcohol having at least one double bond; afatty acid having at least one double bond; a branched fatty alcohol; abranched fatty acid; a fatty acid substituted with a hydroxyl group; anda mixture of any two or more thereof.
 29. The composition of claim 28,wherein the foam adjuvant is selected from the group consisting of cetylalcohol, stearyl alcohol, cetostearyl alcohol, and a mixture thereof.30. The composition of claim 21, wherein the carrier further comprisesan active agent.
 31. The composition of claim 30, wherein the activeagent is selected from the group consisting of an anti-infective, anantibiotic, an antibacterial agent, an antifungal agent, an antiviralagent, an antiparasitic agent, an steroidal antiinflammatory agent, animmunosuppressive agent, an immunomodulator, an immunoregulating agent,a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, avitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, avitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, avitamin F derivative, vitamin K, a vitamin K derivative, a wound healingagent, a disinfectant, an anesthetic, an antiallergic agent, an alphahydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, aprotein, a peptide, a neuropeptide, an allergen, an immunogenicsubstance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylicacid, azelaic acid, sebacic acid, adipic acid, fumaric acid, a retinoid,an antiproliferative agent, an anticancer agent, a photodynamic therapyagent, an anti-wrinkle agent, a radical scavenger, a metal oxide,titanium dioxide, zinc oxide, zirconium oxide, iron oxide, siliconeoxide, an anti wrinkle agent, a skin whitening agent, a skin protectiveagent, a masking agent, an anti-wart agent, a refatting agent, alubricating agent, and a mixture of any two or more thereof.
 32. Thecomposition of claim 21, wherein the oil globules have an average sizeselected from the group consisting of (i) about 40 nm to about 1,000 nm;(ii) about 40 nm to about 500 nm; (iii) about 40 nm to about 200 nm;(iv) about 40 nm to about 100 nm; (v) less than about 500 nm; (vi) lessthan about 200 nm; and (vii) less than about 100 nm.
 33. The compositionof claim 21, wherein the breakable foam has a density selected from thegroup consisting of (i) less than about 0.12 g/mL; (ii) between about0.02 g/mL and about 0.12 g/mL; (iii) between about 0,04 g/mL and about0.10 g/mL; and (iv) between about 0.06 g/mL and about 0.10 g/mL.
 34. Thecomposition of claim 23, wherein the emollient is diisopropyl adipate.35. The composition of claim 24, wherein the hydrophobic solvent ismineral oil.
 36. The composition of claim 35, wherein the carriercomprises a mixture of mineral oil and the emollient in a ratio between2:8 and 8:2 on a weight basis.
 37. A method of promoting penetration ofan active agent into a skin or a mucosal membrane, comprising a.releasing the nano-emulsion composition of claim 30 from the pressurizedcontainer; b. applying the resultant breakable foam obtained from thecomposition to a skin or mucosal membrane; and c. spreading the foam soit is absorbed into the skin or mucosal membrane.
 38. A method oftreating or alleviating a disorder of a skin, body cavity, and/ormucosal surface, comprising topically administering a breakable foamproduced from the composition of claim 30 to a subject having saiddisorder, wherein: (a) the active agent comprises an antifungal agentand the disorder is an fungal disorder; or (b) the active agentcomprises a retinoid and the disease is a sebaceous gland disorder. 39.A method of producing a foam composition having improved foam bubblesize comprising: (i) providing an oil in water emulsion formulation,wherein the emulsion comprises (a) oil globules; (b) about 0.1% to about5% by weight of at least one stabilizing agent selected from the groupconsisting of a non-ionic surfactant, an ionic surfactant, and apolymeric agent; and (c) water; (ii) subjecting the emulsion to highpressure mechanical stress to produce a nano emulsion; and (iii) fillinga sealed pressurized container with the nano emulsion, wherein thecontainer further comprises a liquefied hydrocarbon gas propellant at aconcentration of about 3% to about 25% by weight of the composition andhas an outlet capable of releasing the nano emulsion as a foam; whereinupon release of the foam, the bubble size is significantly greater thanthe bubble size of a foam from an oil in water emulsion formulation thatis not subjected to high pressure mechanical stress to produce a nanoemulsion.
 40. The composition of claim 21, wherein the carrier comprisesone or more of a hydrophobic solvent, a polar solvent, an emollient, anda mixture thereof, at a concentration of about 2% to about 5% by weightof the carrier.
 41. The composition of claim 21, wherein the carriercomprises one or more of a hydrophobic solvent, a polar solvent, anemollient, and a mixture thereof, at a concentration of about 5% toabout 10% by weight of the carrier.
 42. The composition of claim 21,wherein the carrier comprises one or more of a hydrophobic solvent, apolar solvent, an emollient, and a mixture thereof, at a concentrationof about 10% to about 20% by weight of the carrier.
 43. The compositionof claim 21, wherein the carrier comprises one or more of a hydrophobicsolvent, a polar solvent, an emollient, and a mixture thereof, at aconcentration of about 20% to about 50% by weight of the carrier.